ABCMdb

ABCA1 p.Cys1477Arg

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Publications

PMID: 22981231 [PubMed] Smith B et al: "Anticancer Activity of the Cholesterol Exporter ABCA1 Gene."

No. Sentence Comment

124 To this end, we utilized two missense mutations of human ABCA1 proteins (Q597R and C1477R) linked to TD and familial hypoalphalipoproteinemia (FHA), which were previously characterized to have diminished cholesterol efflux activity (Singaraja et al., 2006). Login to comment

PMID: 21920460 [PubMed] Liu Y et al: "Regulation of ABCA1 functions by signaling pathways."

No. Sentence Comment

109 Significantly, one naturally-occurring mutation of ABCA1 associated with Tangier disease, C1477R, severely reduces apoA-I-mediated cAMP production, ABCA1 phosphorylation and apoA-I-mediated lipid efflux, suggesting that direct interaction of apoA-I with a functional ABCA1 is required for the activation of cAMP/PKA pathway by apoA-I. Login to comment

PMID: 21875686 [PubMed] Tietjen I et al: "Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT."

No. Sentence Comment

117 COOHA B T929I H2N R587W B A M1091T C1477R K776N N935S S1181F IVS24+1 G>C V2244I R282X D571G M640L S930F M968T R1615WIVS16-5 CA>del ABCA1 Transmembrane domain ATP-binding domain Q597R A) AA 1 AA 267 K130del L202P 74 90 98 112 122 145 167 189 211 215 233 253 APOA1 Negative charge domain Alpha-helix E222K E134DT37M 140 178 206 41127 104 121 165 200 229 360 391 Y135N V246F 127 206 369 401 Catalytic triad R322C L338H V371MV52M Y107X A117T T147I V333M Phe Leu Asp His AA 1 AA 440 R159Q I202T LCAT Alpha helixBeta sheet B) 419I.Tietjenetal./BiochimicaetBiophysicaActa1821(2012)416-424 3.4. Login to comment

PMID: 21554545 [PubMed] Nagao K et al: "Function and regulation of ABCA1--membrane meso-domain organization and reorganization."

No. Sentence Comment

80 This group is represented by the C1477R mutant of the second ECD (Table 2). Login to comment
81 Although C1477R mutant is expressed in the plasma membrane like wild-type ABCA1, apoA-I binding is abolished [9,10,49,50]. Login to comment

PMID: 21420943 [PubMed] Daniil G et al: "Characterization of antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations of HDL from family subjects with monogenic low HDL disorders."

No. Sentence Comment

56 Subjects We examined serum obtained from 3 heterozygotes for the apoA-I (NM_000039) mutation p.L202P (n=3; mutation was previously denoted as L178P [14]), 6 heterozygotes for ABCA1 (NM_005502) mutations(p.C1477R,n=3;p.L1056P,n=3),2compoundheterozygotes for ABCA1 mutations (p.C1477R/IVS25+1GNC; p.Q1038X/p.N1800H), 1 homozygote for the ABCA1 mutation p.L1056P, 12 heterozygotes for LCAT (NM_000229) mutations (p.P34Q, n=1; p.Y107X, n=1; p.T147I, n=4; p.N155D, n=2; p.I202T, n=1; p.R322C, n=2, p.V333M, n=1), 3 compound heterozygotes for the LCAT mutation p.T147I/IVS4-22TNC and 1 homozygote for the LCAT mutation p.N155D. Login to comment
150 Male/female TC HDL-c apoA-I apoA-II LDL-c apoB TG apoA-I mutation carriers Unaffected (n=3) 1/2 179±27 45±3 163±13 30±1 131±22 97±15 97±25 Heterozygotes (n=3) 1/2 141±12* 20±14* 87±38* 19±6* 113±5 85±6 97±45 ABCA1 mutation carriers Unaffected (n=8) 4/4 171±56 57±15 160±29 30±4 111±23 84±12 85±20 Heterozygotes (n=6) 3/3 179±64 37±7** 124±12** 28±2 129±35 98±22 90±44 Compound heterozygote 1c (n=1) 1/0 54 6 4 2 44 75 138 Compound heterozygote 2d (n=1) 0/1 220 3 7 ndb 173 192 387 Homozygote (n=1) 0/1 63 0.8 nd nd 61 81 87 LCAT mutation carriers Unaffected (n=7) 5/2 199±32 49±13 166±19 31±2 134±28 100±20 123±58 Heterozygotes (n=12) 8/4 166±47 32±11** 122±27*** 26±5* 122±38 97±28 115±49 Compound heterozygotes (n=3) 0/3 140±24* 5±1*** 48±8*** 3.8±0.3*** 118±17 102±27 244±103* Homozygote (n=1) 1/0 107 3 58 4 77 118 279 a Values presented as mean±SD (mg/dl); b nd, not detectable; c ABCA1[p.C1477R/IVS25+1GNC]; d ABCA1[p.Q1038X/ p.N1800H]. Login to comment
162 HDL from heterozygotes for ABCA1 mutations (p.C1477R, p.L1056P), incubated in the absence or presence of LDL, increased the fluorescence signal by 39% (p=0.043) and 41% (p=0.029), respectively, compared to controls (Fig. 2A). Login to comment
163 A previous study has shown that heterozygotes for ABCA1 mutation p.C1477R, but not for ABCA1 mutation p.L1056P, have increased CAD compared to unaffected family members [24,25]. Login to comment
164 These observations may be related to the current finding (although the number of analyzed samples is small) that HDL from heterozygotes for ABCA1 mutation p.C1477R was more oxidized and contained higher MDA levels compared to HDL from heterozygotes for ABCA1 mutation p. L1056P (Fig. 2A, B). Login to comment
166 Compound heterozygotes for ABCA1 mutations * * 0 10000 20000 30000 40000 50000 60000 70000 L1056P L1056P C1477R C1477R ** ** C1477R/ IVS25+1G>C Q1038X/ N1800H C1477R/ IVS25+1G>C Q1038X/ N1800H 0.0 2.5 5.0 7.5 10.0 SAA/HDL-c(RLU) ** 0 10 20 30 40 *** 0 1 2 3 PAF-AHactivity (nmolCE/h) A B C D * ** HDL C HDL Het HDL Com HDL Hom HDL C HDL Het HDL Com HDL Hom HDL C HDL Het HDL Com HDL Hom DCF LDL HDL C HDL HetHDL C +LDL HDL Het + LDL HDL Com HDL Com +LDL Fluoresence(AU) MDA/HDL-c(RLU) Fig. 2. Login to comment
176 p.C1477R/ IVS25+1GNC and a homozygote for ABCA1 mutation p.L1056P presented with CAD [24,25]. Login to comment
147 Male/female TC HDL-c apoA-I apoA-II LDL-c apoB TG apoA-I mutation carriers Unaffected (n=3) 1/2 179&#b1;27 45&#b1;3 163&#b1;13 30&#b1;1 131&#b1;22 97&#b1;15 97&#b1;25 Heterozygotes (n=3) 1/2 141&#b1;12* 20&#b1;14* 87&#b1;38* 19&#b1;6* 113&#b1;5 85&#b1;6 97&#b1;45 ABCA1 mutation carriers Unaffected (n=8) 4/4 171&#b1;56 57&#b1;15 160&#b1;29 30&#b1;4 111&#b1;23 84&#b1;12 85&#b1;20 Heterozygotes (n=6) 3/3 179&#b1;64 37&#b1;7** 124&#b1;12** 28&#b1;2 129&#b1;35 98&#b1;22 90&#b1;44 Compound heterozygote 1c (n=1) 1/0 54 6 4 2 44 75 138 Compound heterozygote 2d (n=1) 0/1 220 3 7 ndb 173 192 387 Homozygote (n=1) 0/1 63 0.8 nd nd 61 81 87 LCAT mutation carriers Unaffected (n=7) 5/2 199&#b1;32 49&#b1;13 166&#b1;19 31&#b1;2 134&#b1;28 100&#b1;20 123&#b1;58 Heterozygotes (n=12) 8/4 166&#b1;47 32&#b1;11** 122&#b1;27*** 26&#b1;5* 122&#b1;38 97&#b1;28 115&#b1;49 Compound heterozygotes (n=3) 0/3 140&#b1;24* 5&#b1;1*** 48&#b1;8*** 3.8&#b1;0.3*** 118&#b1;17 102&#b1;27 244&#b1;103* Homozygote (n=1) 1/0 107 3 58 4 77 118 279 a Values presented as mean&#b1;SD (mg/dl); b nd, not detectable; c ABCA1[p.C1477R/IVS25+1GNC]; d ABCA1[p.Q1038X/ p.N1800H]. Login to comment
159 HDL from heterozygotes for ABCA1 mutations (p.C1477R, p.L1056P), incubated in the absence or presence of LDL, increased the fluorescence signal by 39% (p=0.043) and 41% (p=0.029), respectively, compared to controls (Fig. 2A). Login to comment
160 A previous study has shown that heterozygotes for ABCA1 mutation p.C1477R, but not for ABCA1 mutation p.L1056P, have increased CAD compared to unaffected family members [24,25]. Login to comment
161 These observations may be related to the current finding (although the number of analyzed samples is small) that HDL from heterozygotes for ABCA1 mutation p.C1477R was more oxidized and contained higher MDA levels compared to HDL from heterozygotes for ABCA1 mutation p. L1056P (Fig. 2A, B). Login to comment
173 p.C1477R/ IVS25+1GNC and a homozygote for ABCA1 mutation p.L1056P presented with CAD [24,25]. Login to comment

PMID: 21130455 [PubMed] Karuna R et al: "Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism."

No. Sentence Comment

63 Mutated gene Number of defective alleles Mutationa Age (year) Cholesterol (mM) HDL-cholesterol (mM) NonHDL-cholesterol (mM) Triglyceride (mM) Number of smokers Dutch APOA1 0 27 ± 14 4.59 ± 0.68 1.16 ± 0.06 3.43 ± 0.63 1.09 ± 0.29 0 1 p.L202P (c.605T > C) 26 ± 17 3.61 ± 0.31 0.51 ± 0.35 3.10 ± 0.06 1.09 ± 0.51 0 ABCA1 0 44 ± 20 4.39 ± 0.89 1.47 ± 0.39 2.92 ± 0.62 0.95 ± 0.22 1 1 p.L1056P (c.3167T > C) or p.C1477R (c.4429T > C) 57 ± 11 4.47 ± 1.08 0.94 ± 0.17 3.53 ± 0.96 1.01 ± 0.05 0 2 p.L1056P (c.3167T > C, homozygote) or p.Q1038X (c.3112C > T) + p.N1800H (c.5398A > C) or p.C1477R (c.4429T > C) + IVS25 + 1G > C 53 ± 10 2.89 ± 2.39 NDb NDb 2.29 ± 1.80 0 LCAT 0 49 ± 9 4.96 ± 0.86 1.33 ± 0.38 3.62 ± 0.97 1.29 ± 0.66 0 1 p.T147I (c.440C > T), p.R322C (c.964C > T), p.N155D (c.463A > G), p.P34Q (c.101C > A), p.Y107X (c.321C > A), p.I202T (c.605T > C) or p.V333M (c.997G > A) 43 ± 13 4.27 ± 1.21 0.81 ± 0.28 3.45 ± 1.08 1.30 ± 0.55 1 2 p.T147I (c.440C > T) + V333M 69 ± 4 3.26 ± 0.19 NDb NDb 2.11 ± 0.49 0 SR-BI 0 54 ± 19 4.77 ± 0.89 1.17 ± 0.33 3.60 ± 0.79 1.21 ± 0.64 0 1 p.P297S (c.889C > T) 45 ± 22 4.46 ± 1.21 1.73 ± 0.56 2.73 ± 0.81 0.97 ± 0.28 1 CETP 0 36 ± 16 4.14 ± 0.51 1.30 ± 0.21 2.85 ± 0.48 0.87 ± 0.40 1 1 IVS7 + 1 (G > T) 39 ± 18 4.20 ± 0.51 1.56 ± 0.29 2.64 ± 0.77 0.76 ± 0.32 1 HL (LIPC) 0 45 ± 19 5.23 ± 0.99 1.61 ± 0.54 3.62 ± 0.90 1.45 ± 1.05 3 1 p.S289F (c.866C > T) 45 ± 15 4.92 ± 1.21 2.00 ± 0.68 2.92 ± 0.86 1.14 ± 0.43 1 Danish Controls 0 50 ± 9 5.84 ± 1.24 1.54 ± 0.24 4.30 ± 1.23 1.34 ± 0.62 1 APOA1 1 p.L168R (c.503T > G) 63 ± 4 4.70 ± 0.28 0.85 ± 0.07 3.85 ± 0.35 1.27 ± 0.70 0 CETP 1 p.S349Y (c.1046C > A) 59 ± 4 6.85 ± 2.05 3.05 ± 1.77 3.80 ± 0.28 0.86 ± 0.23 1 Values represent mean ± SD. Login to comment
62 Mutated gene Number of defective alleles Mutationa Age (year) Cholesterol (mM) HDL-cholesterol (mM) NonHDL-cholesterol (mM) Triglyceride (mM) Number of smokers Dutch APOA1 0 27 &#b1; 14 4.59 &#b1; 0.68 1.16 &#b1; 0.06 3.43 &#b1; 0.63 1.09 &#b1; 0.29 0 1 p.L202P (c.605T > C) 26 &#b1; 17 3.61 &#b1; 0.31 0.51 &#b1; 0.35 3.10 &#b1; 0.06 1.09 &#b1; 0.51 0 ABCA1 0 44 &#b1; 20 4.39 &#b1; 0.89 1.47 &#b1; 0.39 2.92 &#b1; 0.62 0.95 &#b1; 0.22 1 1 p.L1056P (c.3167T > C) or p.C1477R (c.4429T > C) 57 &#b1; 11 4.47 &#b1; 1.08 0.94 &#b1; 0.17 3.53 &#b1; 0.96 1.01 &#b1; 0.05 0 2 p.L1056P (c.3167T > C, homozygote) or p.Q1038X (c.3112C > T) + p.N1800H (c.5398A > C) or p.C1477R (c.4429T > C) + IVS25 + 1G > C 53 &#b1; 10 2.89 &#b1; 2.39 NDb NDb 2.29 &#b1; 1.80 0 LCAT 0 49 &#b1; 9 4.96 &#b1; 0.86 1.33 &#b1; 0.38 3.62 &#b1; 0.97 1.29 &#b1; 0.66 0 1 p.T147I (c.440C > T), p.R322C (c.964C > T), p.N155D (c.463A > G), p.P34Q (c.101C > A), p.Y107X (c.321C > A), p.I202T (c.605T > C) or p.V333M (c.997G > A) 43 &#b1; 13 4.27 &#b1; 1.21 0.81 &#b1; 0.28 3.45 &#b1; 1.08 1.30 &#b1; 0.55 1 2 p.T147I (c.440C > T) + V333M 69 &#b1; 4 3.26 &#b1; 0.19 NDb NDb 2.11 &#b1; 0.49 0 SR-BI 0 54 &#b1; 19 4.77 &#b1; 0.89 1.17 &#b1; 0.33 3.60 &#b1; 0.79 1.21 &#b1; 0.64 0 1 p.P297S (c.889C > T) 45 &#b1; 22 4.46 &#b1; 1.21 1.73 &#b1; 0.56 2.73 &#b1; 0.81 0.97 &#b1; 0.28 1 CETP 0 36 &#b1; 16 4.14 &#b1; 0.51 1.30 &#b1; 0.21 2.85 &#b1; 0.48 0.87 &#b1; 0.40 1 1 IVS7 + 1 (G > T) 39 &#b1; 18 4.20 &#b1; 0.51 1.56 &#b1; 0.29 2.64 &#b1; 0.77 0.76 &#b1; 0.32 1 HL (LIPC) 0 45 &#b1; 19 5.23 &#b1; 0.99 1.61 &#b1; 0.54 3.62 &#b1; 0.90 1.45 &#b1; 1.05 3 1 p.S289F (c.866C > T) 45 &#b1; 15 4.92 &#b1; 1.21 2.00 &#b1; 0.68 2.92 &#b1; 0.86 1.14 &#b1; 0.43 1 Danish Controls 0 50 &#b1; 9 5.84 &#b1; 1.24 1.54 &#b1; 0.24 4.30 &#b1; 1.23 1.34 &#b1; 0.62 1 APOA1 1 p.L168R (c.503T > G) 63 &#b1; 4 4.70 &#b1; 0.28 0.85 &#b1; 0.07 3.85 &#b1; 0.35 1.27 &#b1; 0.70 0 CETP 1 p.S349Y (c.1046C > A) 59 &#b1; 4 6.85 &#b1; 2.05 3.05 &#b1; 1.77 3.80 &#b1; 0.28 0.86 &#b1; 0.23 1 Values represent mean &#b1; SD. Login to comment

PMID: 20880529 [PubMed] Candini C et al: "Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol."

No. Sentence Comment

76 Patients (gender, age) Amino acida (nucleotidea ) change TC TG LDL-c HDL-c Clinical manifestations of TD CVD Other relevant clinical data Homozygotes Patient 1 (female, 42) p.L1056P (c.3167T > C) 2.4 0.9 1.99 <0.10 Absent CAD Thrombocytopenia Patient 2 (male, 40) p.Wl747X (c.5240G > A) 1.76 1.93 0.52 0.1-0.3 Neuropathy, splenomegaly, thrombocytopenia Mild stenosis (20-30%) of coronary arteries None Patient 3 (male, 55) p.F593L (c.1779C > G) 4.4 1.4 3.6 <0.10 Absent CAD None p.E1253K (c.3757G > A) Compound heterozygotes Patient 4 (female, 63) p.Q1038X (c.3112C > T) 6.68 2.72 5.4 <0.10 Absent None None p.N1800H (c.5398A > C) [32] Patient 5 (female, 28) p.T1512M (c.4535C > T) 4.42 1.83 3.46 0.1 Absent None None p.N1800H (c.5398A > C) [32] p.C978fsX988 (c.2934delT) Patient 6 (female, 17) p.D575G (c.1724A > G) 4.96 2.84 4.35 <0.10 Absent None DM1 p.C1941R(c.5821T > C) Heterozygotes Patient 7 (male, 42) p.S100C (c.299C > G) 8.5 8.7 4.3 0.3 N.A. None None Patient 8 (male, 58) p.E1172D (c.3516G > C) [33] 6.4 2.7 4.1 0.9 N.A. None None Patient 9 (male, 35) p.S1181F (c.3542C > T) [17] 2.9 0.31 1.88 0.88 N.A. None None Patient 10 (male, 48) p.C1477R (c.4429T > C) [13] 2.01 1.4 0.92 0.46 N.A. CAD None Patient 11 (male, 68) p.V1858A (c.5573T > C) 4.9 3.78 2.41 0.75 N.A. CAD None Patient 12 (female, 36) p.N1800H (c.5398A > C) [32] 4.6 1.2 4 <0.10 N.A. None DM2, obesity Patient 13 (male, 67) p.R282X (c.844C > T) [34] 3.2 1.21 2.14 0.51 N.A. None DM2 Patient 14 (female, 42) p.W424X (c.1272G > A) 2.07 1.04 1.39 0.21 N.A. None None Patient 15 (female, 52) N.A. - (IVS11 - 1G > A) 5.51 3.51 3.28 0.56 N.A. None Hypothyroidism, hypertension Patient 16 (female, 54) N.A. - (IVS48 + 2T > C) 3.29 1.92 1.94 0.49 N.A. None DM2, hypertension a Nomenclature based on guidelines of Human Genome Variation Society. Login to comment
89 In ABCA1, we identified 14 novel and 5 known genetic variations in 16 subjects including one frameshift (p.C978fsX988), 2 splice-site (IVS11-1G > C and IVS48 + 2T > C), 4 nonsense (p.R282X, p.W424X, p.Q1038X, p.Wl747X) and 12 missense variations (p.S100C, p.D575G, p.F593L, p.L1056P, p.E1172D, p.S1181F, p.E1253K, p.C1477R, p.T1512M, p.N1800H, p.V1858A, p.C1941R). Login to comment

PMID: 20067955 [PubMed] Vergeer M et al: "Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction."

No. Sentence Comment

46 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
48 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
93 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment
103 This group consisted of four C1477R carriers, two M1091T carriers, one L996P carrier, one Q978X carrier, and eight control subjects. Login to comment
47 Subjects included in the present study were heterozygous carriers of the following extremely rare ABCA1 mutations: C1477R, M1091T, and R587W (4,7-10) and L996P and Q978X (C. Candini et al., manuscript in preparation). Login to comment
49 C1477R has been reported in nine heterozygous individuals, M1091T in four individuals, and R587W in seven individuals (11). Login to comment
95 Carriers were recruited from five different families (four C1477R carriers, three M1091T carriers, three R587W carriers, four L996P carriers, and one Q978X carrier); family control subjects were siblings, cousins, or partners of a carrier. Login to comment
105 This group consisted of four C1477R carriers, two M1091T carriers, one L996P carrier, one Q978X carrier, and eight control subjects. Login to comment

PMID: 19765707 [PubMed] Cameron J et al: "Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C."

No. Sentence Comment

121 Mutations C1477R and S1506L affecting residues in this loop, have been found to have no effect on the transport of ABCA1 [21], but the mutant proteins encoded by the two mutant alleles interacted much weaker with apoA-I than normal. Login to comment
122 Singaraja et al. [22] also showed C1477R-ABCA1 to be present at the cell surface to a similar degree as WT-ABCA1. Login to comment
119 Mutations C1477R and S1506L affecting residues in this loop, have been found to have no effect on the transport of ABCA1 [21], but the mutant proteins encoded by the two mutant alleles interacted much weaker with apoA-I than normal. Login to comment
120 Singaraja et al. [22] also showed C1477R-ABCA1 to be present at the cell surface to a similar degree as WT-ABCA1. Login to comment

PMID: 20656214 [PubMed] Kang MH et al: "Adenosine-triphosphate-binding cassette transporter-1 trafficking and function."

No. Sentence Comment

135 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 45TCM Vol. 20, No. 2, Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment
136 Table 2. Summary of ABCA1 domains involved in trafficking and function Domain Amino acids Role Effect on ABCA1 TD mutations in domain Reference NH2 signal anchor sequence 1-60 Proper insertion of ABCA1 into membrane in a type II orientation ABCA1 protein expression, proper glycosylation Fitzgerald et al. 2001 PEST sequence 1283-1306 Target for calpain protease Controls cell-surface concentration of ABCA1 and ABCA1 degradation D1289N, 1284X Wang et al. 2003 "NDF6F1" sequence 1311-1450 ApoA-I binding ApoA-I binding increases ABCA1 stability and cell-surface expression L1379F Mukhamedova et al. 2007 PDZ binding motif 2259-2261 Binding site for PDZ-containing proteins Interactions with PDZ proteins stabilize ABCA1 Munehira et al. 2004, Okuhira et al. 2005 Table 3. Summary of ABCA1 posttranslational modifications involved in trafficking and function Posttranslational modification Amino acids Effect on ABCA1 TD mutations Reference Disulfide bond formation C75, C309, C1463, C1465, C1477 Two disulfide bonds formed between the Nand C-terminal halves of ABCA1 are required for ABCA1 to be fully functional C1477R Hozoji et al. 2009 Glycosylation N98, N400, N489, N1504, N1637 (predicted) Unknown, but glycosylation often plays a role in proper protein folding, stability, and trafficking Bungert et al. 2001 Palmitoylation C3, C23, C1110, C1111 Localization of ABCA1 at the PM Singaraja et al. 2009 Phosphorylation T1286, T1305 Are constitutively phosphorylated; the dephosphorylation of these residues increases ABCA1 stability Martinez et al. 2003 Once proteins arrive at the trans-Golgi network (TGN), they are sorted for delivery to multiple destinations including the PM, endosomes, or involvement in retrograde transport. Login to comment

PMID: 19344898 [PubMed] Maekawa M et al: "A novel missense mutation of ABCA1 in transmembrane alpha-helix in a Japanese patient with Tangier disease."

No. Sentence Comment

168 To our knowledge, there is only one case with missense mutation resulting in the substitution of cysteine, i.e., C1477R [2]. Login to comment
169 The C1477R mutant can be expressed on the cell surface normally, but fails to bind to apo A-I unlike C1660R [18]. Login to comment
170 This difference may reflect the localization of the mutants: C1477R is in the extracellular loop and C1660R is in the transmembrane domain. Login to comment

PMID: 19258317 [PubMed] Hozoji M et al: "Formation of two intramolecular disulfide bonds is necessary for ApoA-I-dependent cholesterol efflux mediated by ABCA1."

No. Sentence Comment

25 Indeed, the Tangier disease mutation C1477R has been reported to abolish apoA-I binding and HDL formation (15-17), and several missense mutations in cysteine residues within ECD1 (C54Y, C75G) and ECD2 (C1488R, C1490Y) of ABCA4 have been linked to Stargardt * Thisworkwassupportedbyagrant-in-aidforscientificresearch(S)fromthe Ministry of Education, Culture, Sports, Science, and Technology of Japan, by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and by the World Premier International Research Center Initiative, Ministry of Education, Culture, Sports, Science, and Technology of Japan. Login to comment

PMID: 19019193 [PubMed] Pisciotta L et al: "Severe HDL deficiency due to novel defects in the ABCA1 transporter."

No. Sentence Comment

197 Previous studies have shown that two missense ABCA1 mutants (p.C1477R and p.S1506L) located in the second extracellular loop, when expressed in transfected cells, exhibited a dramatic reduction in the interaction capacity with Apo A-I [27]. Login to comment

PMID: 18776170 [PubMed] Vaughan AM et al: "ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation."

No. Sentence Comment

49 the first extracellular loop (V399A, R587W, W590S, and Q597R), two were in the second extracellular loop (C1477R and I1517R), and one was in the Walker A motif of the first nucleotide binding domain (A937V, NBD1) (Fig. 1). Login to comment
96 Fitzgerald et al. (24) reported similar cell surface localizations for mutants R587W, W590S, Q597R, and C1477R. Login to comment
95 Fitzgerald et al. (24) reported similar cell surface localizations for mutants R587W, W590S, Q597R, and C1477R. Login to comment

PMID: 18706283 [PubMed] Iatan I et al: "Effect of ABCA1 mutations on risk for myocardial infarction."

No. Sentence Comment

119 Genetic variation in ABCA1 and risk of myocardial infarction Study* / year Population screened HDL-C, mmol/L ABCA1 variants Conclusions Clee et al. [28] / 2000 Within 11 TD families: Del L693, R2144X † , Del E,D1893,94 † , R909X, M1091T † , P2150L † , ivs25+1G→C, Del C6825→2145X, CTC6952- 4TT→2203X, C1477R, Q597R, T929I ABCA1 heterozygous patients had a 40%-45% decrease in HDL-C and a greater than threefold increased risk of CHD versus unaffected individuals. Login to comment

PMID: 18218626 [PubMed] Hassan HH et al: "Quantitative analysis of ABCA1-dependent compartmentalization and trafficking of apolipoprotein A-I: implications for determining cellular kinetics of nascent high density lipoprotein biogenesis."

No. Sentence Comment

7 Such endocytosis was impaired by naturally occurring mutations of ABCA1 (Q597R and C1477R). Login to comment
35 EXPERIMENTAL PROCEDURES Patient Selection-For this study, we selected fibroblasts from three normal control subjects and two patients with TD (homozygous for Q597R at the ABCA1 gene and compound heterozygous for C1477R as described previously (12)). Login to comment
71 Cellular Compartmentalization and Trafficking of ApoA-I/ABCA1 APRIL 25, 2008•VOLUME 283•NUMBER 17 JOURNAL OF BIOLOGICAL CHEMISTRY 11165 Dissociation of 125 I-ApoA-I from Intact Cells-BHK-ABCA1, normal human fibroblasts, or fibroblasts with ABCA1 mutations (Q597R and C1477R) from Tangier disease subjects were used. Login to comment
174 Similar results were obtained with normal fibroblasts but not TD mutants (Q597R and C1477R). Login to comment
176 Furthermore, we found that apoA-I-mediated ABCA1 internalization was impaired in the ABCA1 mutant (C1477R) associated with TD (data not shown). Login to comment
36 EXPERIMENTAL PROCEDURES Patient Selection-For this study, we selected fibroblasts from three normal control subjects and two patients with TD (homozygous for Q597R at the ABCA1 gene and compound heterozygous for C1477R as described previously (12)). Login to comment
73 Cellular Compartmentalization and Trafficking of ApoA-I/ABCA1 APRIL 25, 2008ߦVOLUME 283ߦNUMBER 17 JOURNAL OF BIOLOGICAL CHEMISTRY 11165 at SEMMELWEIS UNIV OF MEDICINE on December 3, Dissociation of 125 I-ApoA-I from Intact Cells-BHK-ABCA1, normal human fibroblasts, or fibroblasts with ABCA1 mutations (Q597R and C1477R) from Tangier disease subjects were used. Login to comment
182 Similar results were obtained with normal fibroblasts but not TD mutants (Q597R and C1477R). Login to comment
185 Furthermore, we found that apoA-I-mediated ABCA1 internalization was impaired in the ABCA1 mutant (C1477R) associated with TD (data not shown). Login to comment

PMID: 17655203 [PubMed] Mukhamedova N et al: "The role of different regions of ATP-binding cassette transporter A1 in cholesterol efflux."

No. Sentence Comment

269 Natural mutations found in the Tangier pedigree, R587W, W590S, Q597R, and S1506L, as well as generated mutant C1477R strongly inhibited cholesterol and phospholipid efflux (28, 35, 36) and, with the exception of W590S, also apoA-I binding (36). Login to comment

PMID: 17303779 [PubMed] Kiss RS et al: "Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects."

No. Sentence Comment

47 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment
42 In ABCA1, a total of 19 nonsynonymous coding sequence variants; some of these we reported previously.22 Of these, 9 sequence variants were common polymorphisms (ie, reported in the literature as common or of similar prevalence in control subjects): P85L, P85A, R219K, V399A, V771M, V825I, I883M, E1172D, R1587K.14,32-35 Another 5 sequence variants, identified here, were previously reported to be disease causing: W590L (reported as W590S)14; C1477F (reported as C1477R)13; S1731C (only found in French-Canadian populations)36; N1800H32; and 1851X.37 Five sequence variants were novel: K199F, H551D, R965C, E1386Q, and D1706N. Login to comment

PMID: 16873719 [PubMed] Singaraja RR et al: "Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro."

No. Sentence Comment

46 Indeed, patients heterozygous for the mutations R587W, Q597R, ⌬L693, N935S, A1046D, C1477R, and R2081W had between 47% and 69% of HDL-C levels of controls (Table). Login to comment
49 In contrast, C1477R, D1289N, and P2150L showed similar distribution to wild-type ABCA1, indicating that these mutants cause defects despite their normal localization at the plasma membrane. Login to comment
55 R2081W, along with the mutants localizing to the plasma membrane by fluorescence, D1289N, C1477R, and P2150L, showed both EndoH resistant and sensitive bands, indicating that they are distributed at the ER and at the Golgi, thus confirming the GFP localization data. Login to comment
59 By contrast, D1289N, C1477R, and P2150L were at the plasma membrane in similar quantities as wild-type ABCA1(Figure 2C), also confirming our previous localization data. Login to comment
70 Interestingly however, C1477R, which localized to the plasma membrane elicited almost no ApoA-I binding (19.04Ϯ3.9%, nϭ3, Pϭ0.0008) (Figure 3A), indicating that although plasma membrane localization of ABCA1 is essential, it is not sufficient for ApoA-I binding. Login to comment
79 A1046D and S1506L showed reduced localization at the plasma membrane, and C1477R, D1289L, and P2150L showed localization at the plasma membrane and intracellularly. Login to comment
82 C1477R, S1506L, and R2081W show both EndoH sensitive and resistant bands indicating localization at both the ER and the plasma membrane. Login to comment
84 D1289N, C1477R, and P2150L showed normal ABCA1 localization at the membrane. Login to comment
87 Of the 3 mutants showing plasma membrane localization, C1477R showed significantly reduced lipid efflux. Login to comment
88 Because C1477R showed diminished cell surface ApoA-I binding, this finding indicates that ApoA-I binding is required for ABCA1-mediated lipid efflux. Login to comment
148 C1477R, however, did reach the plasma membrane, similar to wild-type ABCA1. Login to comment
150 The defect in the C1477R mutant suggests that although plasma membrane localization is critical for lipid efflux, clearly other mechanisms must result in the failure to recruit ApoA-I. Login to comment
151 C1477R is localized within the second large extracellular loop in ABCA1, and studies in the related transporter ABCA4 revealed that its 2 large extracellular loops interact with each other through disulfide bonds.26 Because ABCA4 and ABCA1 are closely related, it is possible that the disrupted cysteine in the second large extracellular loop in ABCA1 may also prevent interaction between the 2 large extracellular loops, which could be essential for cell surface ApoA-I binding and lipid efflux. Login to comment

PMID: 16709568 [PubMed] Trompier D et al: "Transition from dimers to higher oligomeric forms occurs during the ATPase cycle of the ABCA1 transporter."

No. Sentence Comment

128 We chose to analyze W590S and C1477R, two Tangier-associated mutations previously characterized and known to differentially affect the ABCA1-induced binding of apoA-I and annexin V (3, 32). Login to comment
133 A:D ratio < 2.5 A:D ratio > 2.5 N-ter 14.86 Ϯ 1.4 19.11 Ϯ 1.3 YABCA1/CABCA1 n ϭ 11 n ϭ 17 Nand C-ter 17.72 Ϯ 2.1 18.91 Ϯ 2.312 C Y ABCA1/ABCA1 Y C n ϭ 11 n ϭ 8 C-ter 11.74 Ϯ 0.85 24.00 Ϯ 1.001 ABCA1Y/ABCA1C n ϭ 29 n ϭ 21 W590S 11.79 Ϯ 1.230 26.54 Ϯ 1.004 W590SY/W590SC n ϭ 12 n ϭ 30 C1477R 13.70 Ϯ 0.7299 26.50 Ϯ 1.462 C1477RY/C1477RC n ϭ 27 n ϭ 22 ABCA1MM 11.83 Ϯ 1.048 26.59 Ϯ 1.591 ABCA1MMY/ABCA1MMC n ϭ 14 n ϭ 15 Oligomerization of the ABCA1 Transporter 20286 constructs supported dimerization since an efficiency of the energy transfer similar to that of wild type and similarly sensitive to variations in acceptor-to-donor ratios was detected (Fig. 4, A and B, and Table 1). Login to comment
134 However, upon fractionation on native PAGE, the lysates of cells transfected with W590S or C1477R showed a higher molecular mass band migrating at Ͼ800 kDa and accounting for 9 and 27%, respectively, of the total ABCA1 signal (Fig. 4C, upper panel), in the absence of any modification of expression levels as shown by the SDS-PAGE analysis (Fig. 4C, lower panel). Login to comment
180 A and B, imaging FRET of cells expressing appropriately tagged W590S or C1477R, two ABCA1 variants associated with Tangier disease and variably affecting the functional readouts associated with ABCA1 expression. Login to comment
127 We chose to analyze W590S and C1477R, two Tangier-associated mutations previously characterized and known to differentially affect the ABCA1-induced binding of apoA-I and annexin V (3, 32). Login to comment
132 A:D ratio < 2.5 A:D ratio > 2.5 N-ter 14.86 afe; 1.4 19.11 afe; 1.3 YABCA1/CABCA1 n afd; 11 n afd; 17 Nand C-ter 17.72 afe; 2.1 18.91 afe; 2.312 C Y ABCA1/ABCA1 Y C n afd; 11 n afd; 8 C-ter 11.74 afe; 0.85 24.00 afe; 1.001 ABCA1Y/ABCA1C n afd; 29 n afd; 21 W590S 11.79 afe; 1.230 26.54 afe; 1.004 W590SY/W590SC n afd; 12 n afd; 30 C1477R 13.70 afe; 0.7299 26.50 afe; 1.462 C1477RY/C1477RC n afd; 27 n afd; 22 ABCA1MM 11.83 afe; 1.048 26.59 afe; 1.591 ABCA1MMY/ABCA1MMC n afd; 14 n afd; 15 Oligomerization of the ABCA1 Transporter 20286 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 281ߦNUMBER 29ߦJULY 21, 2006 at SEMMELWEIS UNIV OF MEDICINE on December 3, constructs supported dimerization since an efficiency of the energy transfer similar to that of wild type and similarly sensitive to variations in acceptor-to-donor ratios was detected (Fig. 4, A and B, and Table 1). Login to comment
179 A and B, imaging FRET of cells expressing appropriately tagged W590S or C1477R, two ABCA1 variants associated with Tangier disease and variably affecting the functional readouts associated with ABCA1 expression. Login to comment

PMID: 16680030 [PubMed] Krimbou L et al: "New insights into the biogenesis of human high-density lipoproteins."

No. Sentence Comment

55 We have previously shown [40], however, that incubation of lipid-free apoE3 with normal fibroblasts generated nascent apoE3/cholesterol/phospholipid complexes that exhibited preb-electrophoretic mobility with a particle size ranging from 9 to 15 nm, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) cells was unable to form such particles. Login to comment
63 We have previously suggested that the high content in phosphatidylinositol [41] or the high number of apoA-I molecules per particle [43] (Fig. 2b, lower panels) may contribute to the increase in the net negative charge of nascent LpA-I and consequently cause 260 Lipid metabolism Table 1 Formation and speciation of nascent apolipoprotein (apo)A-I-containing particles in various cell lines Cell type Pre-b1-LpA-I a-LpA-I Macrophages monocyte-derived þ þ THP-1 þ þ Hepatocytes HepG2 (apoA-I endo, exo) þ þ primary mouse (apoA-I endo) þ þ CaCo-2 (apoA-I endo, exo) - þ Fibroblasts normal - þ Tangier (Q597R) - - Tangier (C1477R) - - HUVEC - - CHO - þ CHO overexpressing ABCA1 - þ The presence of pre-b1-LpA-I and a-LpA-I generated by different cell lines was determined by two-dimensional polyacrylamide nondenaturing gradient gel electrophoresis based on our previous study [28]. Login to comment

PMID: 16443932 [PubMed] Nofer JR et al: "Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter."

No. Sentence Comment

192 Another ABCA1 variant, C1477R, was shown by Haidar et al. (8) to be fully ineffective at mediating apoA-I-dependent cAMP formation and effluxing cholesterol, despite there being only partially decreased apoA-I binding. Login to comment
190 Another ABCA1 variant, C1477R, was shown by Haidar et al. (8) to be fully ineffective at mediating apoA-I-dependent cAMP formation and effluxing cholesterol, despite there being only partially decreased apoA-I binding. Login to comment

PMID: 16501936 [PubMed] Zannis VI et al: "Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL."

No. Sentence Comment

147 In vitro analysis of the effects on apoA-I/ABCA1 interactions (cross-linking assay) by mutations in ABCA1 that are found in Tangier disease patients and diminish lipid efflux [71] showed that cross-linking was dramatically reduced to 5-10% of the WT control for three mutants (Gln597Arg, Cys1477Arg, and Ser1506Leu), reduced by 50% for the Arg587Trp mutant, and was remarkably increased to 125% of control for the Trp590Ser mutant [71]. Login to comment

PMID: 16704350 [PubMed] Brunham LR et al: "Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis."

No. Sentence Comment

555 Since a complete loss of function allele would be expected to result in a 50% reduction in HDL levels, a greater than 50% reduction in HDL is most likely explained by a dominant negative allele, in which TABLE 3 Patient phenotypes associated with heterozygous ABCA1 mutations Mutation HDL (mmol/L) HDL (% of control) Number of patients M1091T 0.48 ± 0.5 30 ± 30 4 G1216V 0.50 40 1 R2144X 0.56 ± 0.2 41 ± 18 12 R282X 0.52 41 1 R909X 0.59 ± 0.3 42 ± 19 5 K776N 0.55 ± 0.1 47 ± 5 2 R587W 0.61 ± 0.1 47 ± 8 7 S364C 0.60 48 1 P1065S 0.80 51 1 c-ter deletion 0.75 53 1 N1800H - 56.5 33 P85L 0.72 ± 0.4 57 ± 33 5 Del693L 0.79 ± 0.2 57 ± 15 8 D1289N 0.80 ± 0.1 59 ± 12 4 R2081W 0.80 ± 0.1 59 ± 12 4 2203X 0.80 ± 0.2 59 ± 20 4 DelED1893,4 0.77 ± 0.2 59 ± 18 8 2145X 0.82 ± 0.1 59 ± 9 4 A1046D 0.70 ± 0.1 60 ± 8 2 Q597R 0.82 ± 0.1 60 ± 5 5 C1477R 0.82 ± 0.2 61 ± 15 9 IVS25 + 1G > C 0.78 ± 0.1 62 ± 12 4 D1099Y 0.83 ± 0.3 63 ± 21 5 1552X 1.00 64 1 F2009S 0.82 ± 0.2 64 ± 19 6 R587W 0.86 ± 0.1 65 ± 17 2 R1068H 0.90 ± 0.3 67 ± 26 9 N935S 1.00 ± 0.3 74 ± 16 7 T929I 1.01 ± 0.2 76 ± 7 8 1284X 1.11 ± 0.2 83 ± 14 5 A937V 1.15 ± 0.6 85 ± 28 2 R1680W 1.22 ± 0.2 87 ± 17 3 635X 1.24 ± 0.5 90 ± 32 7 W590S 1.32 ± 0.6 103 ± 46 15 the mutant protein actually interferes with the activity of the remaining wild-type protein. Login to comment

PMID: 16429166 [PubMed] Brunham LR et al: "Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene."

No. Sentence Comment

48 This SNP has been reported to be associated with decreased HDL cholesterol and increased severity of atherosclerosis in Table 1. subPSEC Scores and Probability of Functional Impairment (Pdeleterious) for ABCA1 Mutations and SNPs Mutations SNPs Variant SubPSEC Pdeleterious Variant subPSEC Pdeleterious P85L À4.62 0.83 R219K À0.57 0.08 H160F À2.79 0.45 V399A À2.26 0.32 R230C À4.27 0.78 V771M À2.86 0.46 A255T À1.81 0.23 T774P À1.99 0.27 E284K À2.34 0.34 K776N À3.53 0.63 Y482C À4.21 0.77 V825I À1.06 0.13 R587W À6.04 0.95 I883M À1.38 0.17 W590S À5.19 0.9 E1172D À1.96 0.26 W590L À4.48 0.82 R1587K À0.58 0.08 Q597R À7.15 0.98 S1731C À4.21 0.77 T929I À4.29 0.78 N935H À8.54 1 N935S À7.53 0.99 A937V À6.6 0.97 A1046D À7.52 0.99 M1091T À3.56 0.64 D1099Y À6.09 0.96 D1289N À2.48 0.37 L1379F À3.81 0.69 C1477R À5.44 0.92 S1506L À5.17 0.9 N1611D À5.69 0.94 R1680W À6.02 0.95 V1704D À3.21 0.55 N1800H À4.23 0.77 R1901S À5.06 0.89 F2009S À2.73 0.43 R2081W À8.08 0.99 P2150L À2.88 0.47 Q2196H À2.74 0.43 DOI: 10.1371/journal.pgen.0010083.t001 PLoS Genetics | www.plosgenetics.org December 2005 | Volume 1 | Issue 6 | e83 0740 Accurate Prediction of ABCA1 Variants Synopsis A major goal of human genetics research is to understand how genetic variation leads to differences in the function of genes. Login to comment
75 Cholesterol Efflux Values for 293 Cells Transfected with ABCA1 Variants and subPSEC and PolyPhen Predictions of the Functional Impact of these Variants Variant Variant Type subPSEC Cholesterol Efflux PolyPhen R2081W Mutation À8.08 21.1 6 21%* Probably damaging N935S Mutation À7.53 29.3 6 13%* Benign A1046D Mutation À7.52 16.8 6 7%* Possibly damaging Q597R Mutation À7.15 17.7 6 14%* Probably damaging R587W Mutation À6.04 31.7 6 33%* Probably damaging C1477R Mutation À5.44 20.5 6 10%* Probably damaging W590S Mutation À5.19 47.1 6 13%* Probably damaging S1506L Mutation À5.17 17.8 6 15%* Probably damaging T929I Mutation À4.29 69.9 6 11%* Possibly damaging N1800H Mutation À4.23 31.3 6 16%* Possibly damaging S1731C SNP À4.21 12.3 6 10%* Possibly damaging M1091T Mutation À3.56 6.9 6 20%* Probably damaging P2150L Mutation À2.88 88.4 6 21% Probably damaging V771M SNP À2.86 145.4 6 33% Benign D1289N Mutation À2.48 137.7 6 86% Benign I883M SNP À1.38 69.1 6 16%* Benign R219K SNP À0.57 103.7 6 21.05 Benign Wild-type - 0.0 100% - *p , 0.01 compared to wild-type ABCA1. Login to comment

PMID: 15897603 [PubMed] Krimbou L et al: "Biogenesis and speciation of nascent apoA-I-containing particles in various cell lines."

No. Sentence Comment

26 MATERIALS AND METHODS Patient selection For the present study, we selected fibroblasts from three normal control subjects and two patients with TD (TD1, homozygous for Q597R at the ABCA1 gene; and TD2, compound heterozygous carrying the mutations C1477R and the splice site G→C in exon 24), as described previously (13, 14). Login to comment
78 As shown in Fig. 1 (upper panels), incubation of stimulated normal fibroblasts, CaCo-2 cells, or CHO-overexpressing ABCA1 (CHO-ABCA1) with 10 ␮g/ml exogenously added 125I-apoA-I for 6 h at 37ЊC followed by the removal of lipid-free apoA-I as described above, and then separation of samples by 2D-PAGGE, generated only ␣-LpA-I with a particle size ranging from 8 to 20 nm, whereas lipid-free apoA-I incubated with either HUVEC or ABCA1 mutant (Q597R) was unable to form such particles. Login to comment
79 In separate experiments, we found that ABCA1 mutant C1477R also failed to form ␣-LpA-I (data not shown). Login to comment

PMID: 15492319 [PubMed] O'Connell BJ et al: "Cellular physiology of cholesterol efflux in vascular endothelial cells."

No. Sentence Comment

27 Normal human skin fibroblasts were obtained by biopsy from a healthy human volunteer, and Tangier fibroblasts were from a patient with compound ABCA1 mutations (ABCA1 C1477R amino acid substitution and an ABCA1 IVS25ϩ1 [G3C] mRNA splice site mutation). Login to comment
22 Normal human skin fibroblasts were obtained by biopsy from a healthy human volunteer, and Tangier fibroblasts were from a patient with compound ABCA1 mutations (ABCA1 C1477R amino acid substitution and an ABCA1 IVS25af9;1 [G3C] mRNA splice site mutation). Login to comment

PMID: 15280376 [PubMed] Denis M et al: "Characterization of oligomeric human ATP binding cassette transporter A1. Potential implications for determining the structure of nascent high density lipoprotein particles."

No. Sentence Comment

182 Interestingly, we found that pre-beta- LpE3 contains four and eight molecules of apoE3 per particle, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) remained in the monomeric form (data not shown). Login to comment
199 Although ABCA1 mutants Q597R and C1477R were found to oligomerize normally (data not shown) and localized to the plasma membrane, they showed the total absence of binding to apoA-I (21, 23). Login to comment
200 These results indicate that the apoA-I lipidation defect observed in either Q597R or C1477R ABCA1 mutants is not caused by impaired oligomerization of ABCA1. Login to comment
201 Furthermore, C1477R, a naturally occurring mutant of ABCA1 in which cysteine 1477 within the second large extracellular loop is replaced with arginine (10), was found to dimerize normally. Login to comment
177 Interestingly, we found that pre-beta- LpE3 contains four and eight molecules of apoE3 per particle, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) remained in the monomeric form (data not shown). Login to comment
194 Although ABCA1 mutants Q597R and C1477R were found to oligomerize normally (data not shown) and localized to the plasma membrane, they showed the total absence of binding to apoA-I (21, 23). Login to comment
195 These results indicate that the apoA-I lipidation defect observed in either Q597R or C1477R ABCA1 mutants is not caused by impaired oligomerization of ABCA1. Login to comment
196 Furthermore, C1477R, a naturally occurring mutant of ABCA1 in which cysteine 1477 within the second large extracellular loop is replaced with arginine (10), was found to dimerize normally. Login to comment

PMID: 15026428 [PubMed] Selva DM et al: "The ATP-binding cassette transporter 1 mediates lipid efflux from Sertoli cells and influences male fertility."

No. Sentence Comment

231 Children of TD fathers TD Patient Mutation Father`s Age Number of Children Youngest Child`s Age Father-Child Age Difference Reference years years years TD1 (III:01) C1477R, splice 43 1 6 36 (17) TD1 (II:5) G1764del-635X 63 2 21 42 (16) TD2 (II:4) 3Ј del-1834X 52 2 Ͻ14 Ͼ38 (16) TD3 (II.4) N935S 66 3 28 38 (16) TD5 (III:4) A877V, W530S 52 1 31 21 (59) II-2 1,284X 62 4 21 41 (60) P R1680W 48 3 5 43 (61) TD, Tangier disease. Login to comment
232 Children of TD fathers TD Patient Mutation Father`s Age Number of Children Youngest Child`s Age Father-Child Age Difference Reference years years years TD1 (III:01) C1477R, splice 43 1 6 36 (17) TD1 (II:5) G1764del-635X 63 2 21 42 (16) TD2 (II:4) 3 del-1834X 52 2 14 38 (16) TD3 (II.4) N935S 66 3 28 38 (16) TD5 (III:4) A877V, W530S 52 1 31 21 (59) II-2 1,284X 62 4 21 41 (60) P R1680W 48 3 5 43 (61) TD, Tangier disease. Login to comment

PMID: 15158913 [PubMed] Albrecht C et al: "Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency."

No. Sentence Comment

215 Two of these, C1477R and S1506L, do not appear to disrupt transport of the protein to the cell surface, as judged by the accessibility of the protein in non-permeabilised cells, but the mutant proteins are unable to mediate cholesterol efflux [38]. Login to comment
214 Two of these, C1477R and S1506L, do not appear to disrupt transport of the protein to the cell surface, as judged by the accessibility of the protein in non-permeabilised cells, but the mutant proteins are unable to mediate cholesterol efflux [38]. Login to comment

PMID: 14754908 [PubMed] Krimbou L et al: "Molecular interactions between apoE and ABCA1: impact on apoE lipidation."

No. Sentence Comment

5 Mutation of ABCA1 associated with Tangier disease (C1477R) abolished both apoE3 binding and apoE3-mediated cholesterol efflux. Login to comment
6 Analysis of apoE3-containing particles generated during the incubation of lipid-free apoE3 with stimulated normal cells showed nascent apoE3/ cholesterol/phospholipid complexes that exhibited prebeta- electrophoretic mobility with a particle size ranging from 9 to 15 nm, whereas lipid-free apoE3 incubated with ABCA1 mutant (C1477R) cells was unable to form such particles. Login to comment
31 MATERIALS AND METHODS Patient selection For the present study, we selected fibroblasts from three normal control subjects and one patient with TD (compound heterozygous carrying the mutations C1477R and the splice site G→C in exon 24) as previously described (16, 20). Login to comment
126 To determine whether naturally occurring mutants of ABCA1 might affect apoE3 binding, cross-linking of apoE3 to mutant ABCA1 (C1477R) was examined. Login to comment
127 As shown in Fig. 4, C1477R mutant abolished both apoE3 cross-linking and apoE3-mediated cholesterol efflux. Login to comment
128 On the other hand, C1477R mutant was found to be present at the plasma membrane, as determined by cell surface biotinylation (data not shown). Login to comment
129 To investigate the nature of apoE3-containing particles generated by ABCA1, stimulated cells from either normal control or TD (C1477R) subjects in 100 mm diameter dishes were incubated with 5 ␮g/ml lipid-free apoE3 in DMEM for 24 h at 37ЊC. Login to comment
175 A: Fibroblasts from a normal control and a Tangier disease (TD) (C1477R) subject were stimulated and incubated with 3 ␮g/ml apoE3. Login to comment
176 Cross-linking, immunoprecipitation, and detection of apoE3 associated with ABCA1 were performed as described in Materials and Methods. B: Fibroblasts from a normal control and a mutant (C1477R) subject were labeled with [3H]cholesterol and cholesterol-loaded, then stimulated for 20 h. Cells were incubated with 10 ␮g/ml apoE3 or apoA-I for 24 h, and cholesterol efflux was determined. Values represent means Ϯ SD from triplicate wells. Login to comment
185 In contrast, apoE3 incubated with TD cells (C1477R) was unable to form such particles (Fig. 5); because this is the plasma HDL-LpE3 size range having prebeta electrophoretic mobility (13), these particles are designated prebeta-LpE3-like particles. Login to comment
188 These results are consistent with our Fig. 5. Characterization of lipidated apoE3-containing particles generated during apoE3 incubation with stimulated fibroblasts from a normal and a TD (C1477R) subject. Login to comment
198 observations that ABCA1 mutation in the second large extracellular loop (C1477R) abolished both apoE3 binding and apoE3-mediated cholesterol efflux (Fig. 4). Login to comment
174 A: Fibroblasts from a normal control and a Tangier disease (TD) (C1477R) subject were stimulated and incubated with 3 g/ml apoE3. Login to comment
184 In contrast, apoE3 incubated with TD cells (C1477R) was unable to form such particles (Fig. 5); because this is the plasma HDL-LpE3 size range having pre electrophoretic mobility (13), these particles are designated pre-LpE3-like particles. Login to comment
187 These results are consistent with our Fig. 5. Characterization of lipidated apoE3-containing particles generated during apoE3 incubation with stimulated fibroblasts from a normal and a TD (C1477R) subject. Login to comment
195 observations that ABCA1 mutation in the second large extracellular loop (C1477R) abolished both apoE3 binding and apoE3-mediated cholesterol efflux (Fig. 4). Login to comment

PMID: 14701824 [PubMed] Haidar B et al: "Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter."

No. Sentence Comment

9 Naturally occurring mutations of ABCA1 associated with Tangier disease (C1477R, 2203X, and 2145X) severely reduced apoA-I-mediated cAMP production, ABCA1 phosphorylation, 125 I-apoA-I binding, and lipid efflux, without affecting forskolin-mediated cAMP elevation. Login to comment
154 The C1477R (TD-1) mutant showed decreased presence at the plasma membrane, relative to the normal transporter (50% or greater reduction); however, the 2154X (TD-3) mutant failed to reach the membrane. Login to comment
200 On the other hand, we have documented previously (8) that 8-Br-cAMP and FRK did not induce ABCA1 phosphorylation in intact fibroblasts from TD-1 (C1477R) as compared with normal cells. Login to comment
208 A, fibroblasts from a normal control (CTR) and TD subjects (TD-1 (C1477R), TD-2 (2203X), and TD-3 (2145X)) (Table I) were stimulated, and ABCA1 was immunoprecipitated and incubated with [␥-32 P]ATP in the absence or presence of the PKA catalytic subunit (PKA-c) as described under "Experimental Procedures." Login to comment
153 The C1477R (TD-1) mutant showed decreased presence at the plasma membrane, relative to the normal transporter (50% or greater reduction); however, the 2154X (TD-3) mutant failed to reach the membrane. Login to comment
198 On the other hand, we have documented previously (8) that 8-Br-cAMP and FRK did not induce ABCA1 phosphorylation in intact fibroblasts from TD-1 (C1477R) as compared with normal cells. Login to comment
206 A, fibroblasts from a normal control (CTR) and TD subjects (TD-1 (C1477R), TD-2 (2203X), and TD-3 (2145X)) (Table I) were stimulated, and ABCA1 was immunoprecipitated and incubated with [ॹ-32 P]ATP in the absence or presence of the PKA catalytic subunit (PKA-c) as described under "Experimental Procedures." Login to comment

PMID: 14746569 [PubMed] Hovingh GK et al: "HDL deficiency and atherosclerosis: lessons from Tangier disease."

No. Sentence Comment

23 This patient proved to be compound heterozygous for two ABCA1 gene mutations: a splicing defect (ivs 25+IG->C) and a missense mutation (C1477R). Login to comment
42 Our data suggest that Table 1 Overview of cases 1 and 2 Case 1 Case 2 Gender Male Male Age 38 52 BMI (kg m)2 ) 26 27 Lipids, lipoproteins and modifying enzymes Total cholesterol (mmol L)1 ) 2.3 4.1 LDL-C (mmol L)1 ) 1.3 2.7 HDL-C (mmol L)1 ) <0.1 <0.1 Triglycerides (mmol L)1 ) 2.0 2.3 ApoAI (g L)1 ) 0.01 0.08 ApoAII (g L)1 ) 0.05 0.16 ApoB (g L)1 ) 0.51 1.26 CETP mass (mg L)1 ) 1.65 2.79 Diagnosis ABCA1 functiona Reduced 90% Reduced 70% ABCA1 gene mutations Compound heterozygous Ivs 25 ¼ IG->C; C1477R Compound heterozygous GG5277,8C; T929I Clinical Clinical manifestation of CAD Premature MI and peripheral vascular disease NO IMT mean femoral and carotid artery 1.21 mm 0.89 mm a Fibroblast cholesterol efflux to apoA-I, compared with control, measured in triplicate. Login to comment

PMID: 14644402 [PubMed] Kuivenhoven JA et al: "Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size."

No. Sentence Comment

45 The proband of family 1 suffered from TD and was found to be compound heterozygote for two ABCA1 gene defects: A missense mutation (T→C at position 4824) resulting in C1477R, and a non-sense defect (IVS25 + 1G to C) that caused differential splicing. Login to comment

PMID: 12763760 [PubMed] Singaraja RR et al: "Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene."

No. Sentence Comment

80 However, failure of binding may also occur because of disruption of residues crucial for this function. Indeed, the variants C1477R and S1506L, which are both localized in the second large extracellular loop, are normally translocated to the plasma membrane but show no ApoA-I binding, indicating that specific amino acids in the large extracellular loops are Figure 4. Login to comment
83 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ⅐ ⅐ ⅐ P R230C R R R P G A255T A A S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ R587W R R R ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ W590S W W W R Q Q597R Q Q Q Q Q ⌬L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ S1506L S S S ⅐ ⅐ ⅐ ⅐ ⅐ ⅐ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N ⌬E1893 E E E D S ⌬D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues. Login to comment
136 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon -1095A/G Promoter ⅐ ⅐ ⅐ -477C/T Promoter ⅐ ⅐ ⅐ -419A/C Promoter ⅐ ⅐ ⅐ -320G/C Promoter ⅐ ⅐ ⅐ -191G/C Promoter ⅐ ⅐ ⅐ C69T 5ЈUTR 1 C117G 5ЈUTR 1 InsG319 5ЈUTR 2 G378C 5ЈUTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment
72 However, failure of binding may also occur because of disruption of residues crucial for this function. Indeed, the variants C1477R and S1506L, which are both localized in the second large extracellular loop, are normally translocated to the plasma membrane but show no ApoA-I binding, indicating that specific amino acids in the large extracellular loops are Figure 4. Login to comment
75 TABLE 2. Conservation of Amino Acid Residues Mutated in Humans Mutation H. sapiens M. musculus G. gallus D. melanogaster C. elegans P85L P P P ዼ ዼ ዼ P R230C R R R P G A255T A A S ዼ ዼ ዼ ዼ ዼ ዼ R587W R R R ዼ ዼ ዼ ዼ ዼ ዼ W590S W W W R Q Q597R Q Q Q Q Q èc;L693 L L L L L T929I T T T T T N935S/H N N N N N A937V A A A A A A1046D A A A A A M1091T M M M M M D1099Y D D D D D D1289L/N D D D D D C1477R C C C ዼ ዼ ዼ ዼ ዼ ዼ S1506L S S S ዼ ዼ ዼ ዼ ዼ ዼ N1611D N N N N S R1680W R R R R R N1800H N N N A W F2009S F F F I M R2081W R R R R R P2150L P P P R N èc;E1893 E E E D S èc;D1894 D D D D D Twenty-three of 24 (95.83%) amino acids affected by mutations are conserved with G. gallus, reflecting the functional importance of these residues. Login to comment
128 Single Nucleotide Polymorphisms in the ABCA1 Gene Nucleotide Amino Acid Exon afa;1095A/G Promoter ዼ ዼ ዼ afa;477C/T Promoter ዼ ዼ ዼ afa;419A/C Promoter ዼ ዼ ዼ afa;320G/C Promoter ዼ ዼ ዼ afa;191G/C Promoter ዼ ዼ ዼ C69T 5b18;UTR 1 C117G 5b18;UTR 1 InsG319 5b18;UTR 2 G378C 5b18;UTR 2 G1051A R219K 7 T1591C V399A 11 G2706A V771M 16 A2715C T774P 16 G2723C K776N 16 G2826A V825I 17 A3044G I883M 18 G3911C E1172D 24 G5255A R1587K 35 C5587G S1731C 38 Singaraja et al Clinical and Biochemical Impact of ABCA1 Variants markers, namely, increased arterial wall thickness and ABCA1-mediated cholesterol efflux, was performed.73 The study group consisted of 30 individuals heterozygous for 4 different missense mutations in the ABCA1 gene, C1477R, M1091T, P2150L, and T929I. Login to comment

PMID: 12840658 [PubMed] Miller M et al: "Genetics of HDL regulation in humans."

No. Sentence Comment

66 TD 1591 T/C 11 V399A extracellular [68] TD 1979 (110bpAlu Ins) 12 truncated truncation [60] TD/FHA 2154 C/T 14 R587W extracellular [67,69] TD 2164 G/C 14 W590S extracellular [61] TD 2185 A/G 14 Q597R extracellular [59,67] TD 2219 G/del 14 truncated, 635X truncated [60,61] FHA 2472-2474 3bp del 15 Del L693 TM domain #3 [59] phosphorylation 2706 G/A 16 V771M extracellular [68] 2715 A/C 16 T774P extracellular [68] 2723 G/C 16 K776N extracellular [68] 2868 G/A 17 V825I TM domain #6 [67,68] TD/FHA 3044 A/G 18 I883M cytoplasmic [68] phosphorylat site FHA 3120 C/T 19 R909X truncation [63,71] TD 3181 C/T 19 T929I cytoplasmic [62] TD 3199 A/G 19 N935S Walker A [61] TD 3205 C/T 19 A937V Walker A [61] TD 3532 C/A 22 A1046D cytoplasmic, Walker A/B [70] FHA 3667 T/C 23 M1091T cytoplasmic [63] 3690 G/T 23 D1099Y cytoplasmic [9] TD 3738 2bp del 23 1145X truncation [66] FHA 3911 G/C 24 E1172D linker/cytoplasmic [68] FHA 4242 4bp del 27 1297X truncated [64] TD 4260 G/A 27 D1289N linker cytoplasm [64,65] TD 4824 T/C 31 C1477R extracellular [59] TD 4912 C/T 32 S1506L extracellular loop #2 [71] TD 5025 ins A 34 A1544S?1552X truncation [70] 5059 T/C 34 I1555T extracellular loop #2 [67] 5155 G/A 35 R1587K extracellular loop #2 [68] FHA 5226 A/G 36 N1611D extracellular loop #2 [75..] 5338 T/C 36 L1648P extracellular loop #2 [67] TD 5443 C/T 37 R1680W cytoplasmic [74.] Login to comment

PMID: 12700344 [PubMed] Hovingh GK et al: "The role of the ABCA1 transporter and cholesterol efflux in familial hypoalphalipoproteinemia."

No. Sentence Comment

81 The two compound heterozygous patients have been described previously [one of the compound heterozygous carriers suffered from a missense mutation (T to C at position 4,369) resulting in a C1477R, and a defect (IVS24 ϩ 1G to C) that caused differential splicing, whereas the other was shown to carry a missense mutation (C to T at position 3,181 resulting in T929I) and a de novo nonsense mutation] (16). Login to comment
80 The two compound heterozygous patients have been described previously [one of the compound heterozygous carriers suffered from a missense mutation (T to C at position 4,369) resulting in a C1477R, and a defect (IVS24 1G to C) that caused differential splicing, whereas the other was shown to carry a missense mutation (C to T at position 3,181 resulting in T929I) and a de novo nonsense mutation] (16). Login to comment

PMID: 12551894 [PubMed] Zha X et al: "Secretory vesicular transport from the Golgi is altered during ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux."

No. Sentence Comment

55 The Tangier patient is a compound heterozygote in which one allele gives the mutation C1477R and the other one is a Gly 3 Cys mutation at an exon/intron boundary, causing a splice site mutation and thus a truncated mRNA (5). Login to comment
54 The Tangier patient is a compound heterozygote in which one allele gives the mutation C1477R and the other one is a Gly 3 Cys mutation at an exon/intron boundary, causing a splice site mutation and thus a truncated mRNA (5). Login to comment

PMID: 12642355 [PubMed] Marcil M et al: "Cellular phospholipid and cholesterol efflux in high-density lipoprotein deficiency."

No. Sentence Comment

85 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 ⌬2017-9 ⌬L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 ⌬5618-23 ⌬ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 ⌬C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment
79 Molecular Characterization of ABCA1 Gene in Study Subjects Cell Lines HDL-C, mmol/L Nucleotide Change Predicted Protein Alteration TD CTL-1 0.10 Exon 30 T4369C; exon 24 splice site G3C C1477R; part of the transcript deleted TD CTL-2 0.15 Exon 13 A1730G Q597R FHD-1 0.40 Exon 14 èc;2017-9 èc;L693 FHD-2 0.18 Exon 48 C6370T R2144X FHD-3 0.39 Exon 41 èc;5618-23 èc;ED1893,4 FHD-4 0.18 Exon 18 C2665T R909X FHD-5 0.10 Exon 23 T3667C M1091T FHD-6 0.57 Exon 49 C6844T P2150L, R587W TD-1 0.03 Exon 48 èc;C6370; ND 2145X TD-2 0.07 ND ND TD-3 0.03 ND 2203X TD-4 0.09 Exon 19 C3181T; ND T929I; ND CTL indicates control. Login to comment

PMID: 12454270 [PubMed] Haidar B et al: "cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts."

No. Sentence Comment

176 Molecular characterization of ABCA1 gene in study subjects Cell Lines HDL-C Nucleotide Change Predicted Protein Alteration mmol/l CTR1 1.63 - - CTR2 1.20 - - FHD1 0.27 Exon 14 ⌬2017-9 ⌬L693 FHD2 0.18 Exon 18 C2665T R909X FHD3 0.39 Exon 41 ⌬5618-23 ⌬ED1893,4 FHD4 0.18 Exon 48 C6370T R2144X FHD5 0.09 Exon 36 GG5277,8C fs 1628G, Q1636X TD1 Ͻ0.1 Exon 30 T4369C; Exon 24 splice site G→C C1477R; Part of the transcript deleted TD2 Ͻ0.1 Exon 13 A1730G Q597R TD3 Ͻ0.1 Exon 48 ⌬C6370; nd 2145X; nd FHD1-5 are heterozygous for the reported mutation; TD1,3 are compound heterozygous and TD2 is homozygous. Login to comment

PMID: 12454269 [PubMed] Rigot V et al: "Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids."

No. Sentence Comment

60 When analyzing double mutants (HA819/ C1477R and HA819/1466), the comparison was carried out between each double and the relevant loss of function single mutant (C1477R and HA1466, respectively). Login to comment
148 This was virtually complete in the case of W590S, Q597R, and ⌬L693, and reduced to one fourth for R587W and C1477R (Table 3). Login to comment
168 C1477R falls into a second class since it is detected at the plasma membrane but elicits a significantly reduced binding of apoA-I as compared with wild-type (33% Ϯ 9, n ϭ 6, P Ͻ 0.01 Table 1). Login to comment
171 Indeed, these variants, while eliciting an apoA-I binding indistinguishable from wild-type ABCA1 (79% Ϯ 5, n ϭ 7, P Ͼ 0.05 and 126% Ϯ 18, n ϭ 6, P Ͼ 0.05 of wild type, respectively) fail to drive both flipping of PS (annexin V binding ϭ 39% Ϯ 11of wild type for R587W, n ϭ 5, P Ͻ 0.05 and 30% Ϯ 9 for W590S, n ϭ 7, P Ͻ 0.01) and membrane release of PL (27% Ϯ 16, n ϭ 3, P Ͻ 0.05 and 16% Ϯ 3, n ϭ 2, P Ͻ 0.01 of wild type, respectively, Table 3), thus indicating that apoA-I binding per se is insufficient for the generation of PL effluxes, which also requires PS flipping. Login to comment
172 HA 819 acts as a suppressive mutations on Tangier C1477R Having observed that we could generate mutant transporters showing opposite behaviors with respect of apoA-I surface binding, we asked which effect could result from the introduction of a gain of function mutation on an hypomorphic mutant allele. Login to comment
173 We thus grafted the HA819, which increases selectively apoA-I binding (151% Ϯ 11 of wild type, n ϭ 4, P Ͻ; 0.05), on HA1466 (apoA-I binding ϭ 27% Ϯ 7 of wild type, n ϭ 9, P Ͻ 0.001), and on C1477R (33% Ϯ 9 of wild type, n ϭ 6, P Ͻ 0.01). Login to comment
174 The latter showed similar levels of annexin V binding (52% Ϯ 10, n ϭ 7 for HA1466 P Ͼ 0.05 and 53% Ϯ 12, n ϭ 9, for C1477R, P Ͼ 0.05). Login to comment
177 In both cases, the presence of an HA tag at position 819 partially and significantly rescued the binding of apoA-I but drove limited and nonsignificant modifications in the annexin V binding with respect to the original loss of function mutation (Table 3; apoA-I binding values reverted to 68% Ϯ 6 for HA819/C1477R, n ϭ 4, P Ͻ 0.05 and to 49% Ϯ 7 for HA819/HA1466, n ϭ 6, P Ͻ 0.05, whereas annexin V binding amounted to 57% Ϯ 15, n ϭ 4, for HA819/ C1477R and 54% Ϯ 12, n ϭ 6 for HA819/HA1466 P Ͼ 0.05). Login to comment
178 In both cases the ability to induce PL effluxes was also significantly increased (HA819/C1477R ϭ 142% Ϯ 2 4, n ϭ 2, P Ͻ 0.01 and HA819/HA1466 ϭ 108% Ϯ 28, n ϭ 4, P Ͻ 0.05). Login to comment
205 Morphological and functional evaluation of Tangier- associated ABCA1 variants Identity SL AnnV St ApoA-I St PL Efflux St % % % R587W PM 39 Ϯ 11(5) a 79 Ϯ 5 (7) a 27 Ϯ 16 (3) a W590S PM 30 Ϯ 9 (7) b 126 Ϯ 18 (6) ns 16 Ϯ 3 (2) b Q597R ER, PM 24 Ϯ 9 (4) b 15 Ϯ 8 (4) c 8 Ϯ 7 (2) b ⌬L693 ER 26 Ϯ 11 (5) a 12 Ϯ 6 (4) c nd C1477R PM 53 Ϯ 12 (9) ns 33 Ϯ 9 (6) b 12 Ϯ 2 (2) b HA819/1466 PM 54 Ϯ 12 (6) ns 49 Ϯ 7 (6) a 108 Ϯ 28 (4) b HA819/C1477R PM 57 Ϯ 15 (4) ns 68 Ϯ 6 (4) a 142 Ϯ 24 (2) b SL, subcellular localization as detected by confocal imaging and confirmed by surface biotynilation; AnnV and ApoA-I, binding of annexin V or apoA-I in cells successfully transfected with the test construct (GFP positive); St, statistical significance. Login to comment
229 Since the presence of disulfide bridges connecting the two halves of the protein has been shown for ABCR and, by extension, suggested for ABCA1, C1477 may well be strategic for the structural configuration of extracellular domains (23); however, considering that the loss of apoA-I binding in C1477R can be rescued by a suppressive mutation in the loop between TM5 and TM6 unable in itself to restore a disulfide bridge, it seems more likely that the coexistence of two discrete modifications in the putative apoA-I docking domain can fine tune its spatial conformation. Login to comment
147 This was virtually complete in the case of W590S, Q597R, and L693, and reduced to one fourth for R587W and C1477R (Table 3). Login to comment
167 C1477R falls into a second class since it is detected at the plasma membrane but elicits a significantly reduced binding of apoA-I as compared with wild-type (33% 9, n 6, P 0.01 Table 1). Login to comment
176 In both cases, the presence of an HA tag at position 819 partially and significantly rescued the binding of apoA-I but drove limited and nonsignificant modifications in the annexin V binding with respect to the original loss of function mutation (Table 3; apoA-I binding values reverted to 68% 6 for HA819/C1477R, n 4, P 0.05 and to 49% 7 for HA819/HA1466, n 6, P 0.05, whereas annexin V binding amounted to 57% 15, n 4, for HA819/ C1477R and 54% 12, n 6 for HA819/HA1466 P 0.05). Login to comment
204 Morphological and functional evaluation of Tangier-associated ABCA1 variants Identity SL AnnV St ApoA-I St PL Efflux St % % % R587W PM 39 11(5) a 79 5 (7) a 27 16 (3) a W590S PM 30 9 (7) b 126 18 (6) ns 16 3 (2) b Q597R ER, PM 24 9 (4) b 15 8 (4) c 8 7 (2) b L693 ER 26 11 (5) a 12 6 (4) c nd C1477R PM 53 12 (9) ns 33 9 (6) b 12 2 (2) b HA819/1466 PM 54 12 (6) ns 49 7 (6) a 108 28 (4) b HA819/C1477R PM 57 15 (4) ns 68 6 (4) a 142 24 (2) b SL, subcellular localization as detected by confocal imaging and confirmed by surface biotynilation; AnnV and ApoA-I, binding of annexin V or apoA-I in cells successfully transfected with the test construct (GFP positive); St, statistical significance. Login to comment
228 Since the presence of disulfide bridges connecting the two halves of the protein has been shown for ABCR and, by extension, suggested for ABCA1, C1477 may well be strategic for the structural configuration of extracellular domains (23); however, considering that the loss of apoA-I binding in C1477R can be rescued by a suppressive mutation in the loop between TM5 and TM6 unable in itself to restore a disulfide bridge, it seems more likely that the coexistence of two discrete modifications in the putative apoA-I docking domain can fine tune its spatial conformation. Login to comment

PMID: 12401893 [PubMed] Wellington CL et al: "Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol."

No. Sentence Comment

131 Expression data by mutation Family Mutation Proteinc Induced/Uninduced HDL-C Net Effluxd mmol/l % of control FHA1 Del L 693 5.95 (0.82) 0.4 79.47 (22.63) FHA2 R2144X 2.45 (0.19) 0.18 64.01 (11.12) FHA3 Del E,D 1893, 1894 7.82 (1.48) 0.39 60.03 (11.85) FHA4 R909X 2.32 (0.52) 0.18 72.28 (18.01) FHA5 M1091T 6.42 (0.29) 0.1 47.24 (3.79) TD1 ivs2511G-C, C1477R 3.46 (0.50) 0.1 2.73 (1.05) TD1-ha C1477R 10.28 (1.07) 0.9 58.14 (5.49) TD3 GG 5277C - 1636 2.89 (0.59) 0.09 23.3 (1.29) TD3-hb T9291 6.65 (0.10) 1.12 51.8 (1.30) TD4 Del C 6825 - 2145X, unidentified 1.14 (0.13) 0.03 17.22 (0) Control None 11.31 (0.68) 1.63 100.00 (7.09) a TD1-h is the heterozygous parent of the TD1 proband. Login to comment

PMID: 12084722 [PubMed] Fitzgerald ML et al: "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I."

No. Sentence Comment

39 DNA Constructs-Five missense mutants of ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) were generated using overlap polymerase chain reaction methods, as described previously (17). Login to comment
70 Missense Mutations in Two Putative Extracellular Loops of ABCA1 Ablate Efflux Activity-Five missense mutations (R587W, W590S, Q597R, C1477R, and S1506L) were introduced into a wild type ABCA1 cDNA using PCR mutagenesis techniques. Login to comment
72 The other two mutations (C1477R and S1506L) fall within the central loop of the protein. Login to comment
116 The cells were transfected with either empty vector (mock), wild type ABCA1 (WT), or ABCA1 constructs carrying the indicated point mutations (R587W, W590S, Q597R, C1477R, and S1506L). Login to comment
119 Absolute apoA-I and medium efflux values, respectively, are as follows: mock, 1.59 Ϯ 0.04% versus 1.21 Ϯ 0.39%; WT, 3.92 Ϯ 0.13% versus 1.9 Ϯ 0.08%; R587W, 1.78 Ϯ 0.11% versus 1.61 Ϯ 0.24%; W590S, 1.92 Ϯ 0.24% versus 1.63 Ϯ 0.08%; Q597R, 1.5 Ϯ 0.14% versus 1.49 Ϯ 0.03%; C1477R, 1.67 Ϯ 0.18% versus 1.52 Ϯ 0.15%; and S1506L, 1.66 Ϯ 0.28% versus 1.6 Ϯ 0.13%. Login to comment
198 Three of the mutants (Q597R, C1477R, and S1506L) had dramatic reductions in their cross-linking efficiency to apoA-I, relative to the wild type transporter (90% or greater reduction). Login to comment
202 DISCUSSION In this study, we have established that several naturally occurring missense mutations in ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) located in the two largest loop domains of the protein (comprising amino acids ϳ44-640 and ϳ1371-1649, respectively) are, in fact, loss-of-function mutations. Login to comment
210 Only one cysteine mutant was utilized in this study (C1477R), and work is currently underway to determine whether this mutation affects the formation of a disulfide linkage in ABCA1. Login to comment
212 Although three of the mutations (Q597R, C1477R, and S1506L) showed no appreciable cross-linking to apoA-I, the R587W mutant had an intermediate activity, and the W590S mutant retained full, if not enhanced, cross-linking to the apoprotein. Login to comment
37 DNA Constructs-Five missense mutants of ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) were generated using overlap polymerase chain reaction methods, as described previously (17). Login to comment
67 Missense Mutations in Two Putative Extracellular Loops of ABCA1 Ablate Efflux Activity-Five missense mutations (R587W, W590S, Q597R, C1477R, and S1506L) were introduced into a wild type ABCA1 cDNA using PCR mutagenesis techniques. Login to comment
69 The other two mutations (C1477R and S1506L) fall within the central loop of the protein. Login to comment
112 The cells were transfected with either empty vector (mock), wild type ABCA1 (WT), or ABCA1 constructs carrying the indicated point mutations (R587W, W590S, Q597R, C1477R, and S1506L). Login to comment
115 Absolute apoA-I and medium efflux values, respectively, are as follows: mock, 1.59 afe; 0.04% versus 1.21 afe; 0.39%; WT, 3.92 afe; 0.13% versus 1.9 afe; 0.08%; R587W, 1.78 afe; 0.11% versus 1.61 afe; 0.24%; W590S, 1.92 afe; 0.24% versus 1.63 afe; 0.08%; Q597R, 1.5 afe; 0.14% versus 1.49 afe; 0.03%; C1477R, 1.67 afe; 0.18% versus 1.52 afe; 0.15%; and S1506L, 1.66 afe; 0.28% versus 1.6 afe; 0.13%. Login to comment
190 Three of the mutants (Q597R, C1477R, and S1506L) had dramatic reductions in their cross-linking efficiency to apoA-I, relative to the wild type transporter (90% or greater reduction). Login to comment
194 DISCUSSION In this study, we have established that several naturally occurring missense mutations in ABCA1 (R587W, W590S, Q597R, C1477R, and S1506L) located in the two largest loop domains of the protein (comprising amino acids b03;44-640 and b03;1371-1649, respectively) are, in fact, loss-of-function mutations. Login to comment
204 Although three of the mutations (Q597R, C1477R, and S1506L) showed no appreciable cross-linking to apoA-I, the R587W mutant had an intermediate activity, and the W590S mutant retained full, if not enhanced, cross-linking to the apoprotein. Login to comment

PMID: 11809185 [PubMed] van Dam MJ et al: "Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study."

No. Sentence Comment

52 The ABCA1 mutations in NL-014 and NL-016, which have been previously described, consist of 4369T→C (C1477R) and 3212T→C (M1091T), respectively.6,9 Mutation carriers from the two newly discovered families with familial hypoalphalipoproteinaemia NL-020 and NL-016 had a 6844C→T (P2150L) and a 3181C→T (T929I) mutation in the ABCA1 gene respectively. Login to comment

PMID: 23136402 [PubMed] Bochem AE et al: "ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden."

No. Sentence Comment

81 Efflux measured in fibroblasts from a heterozygous p.Cys1477Arg carrier was used as a positive control since the efflux capacity has consistently been shown to be impaired.19,27 One patient compound heterozygous for mutation p.Arg579Gln and p.Val771Met was included. Login to comment

PMID: 23543682 [PubMed] Lyssenko NN et al: "Factors controlling nascent high-density lipoprotein particle heterogeneity: ATP-binding cassette transporter A1 activity and cell lipid and apolipoprotein AI availability."

No. Sentence Comment

37 MATERIALS AND METHODS Cell culture and biogenesis of nascent HDL BHK-ABCA1, BHK-ABCA1(W590S), and BHK-ABCA1(C1477R) cells expressing human wild-type or mutant ABCA1 have been previously described (36, 37). Login to comment
166 Mutations in ABCA1 that compromise its functionality shift nascent HDL production to the smaller particle species W590S and C1477R are naturally occurring mutations in human ABCA1 that impair its functionality and cause Tangier disease (49) but do not affect its subcellular localization or expression levels (37). Login to comment
167 To determine how deficiency in ABCA1 functionality affects size heterogeneity of nascent HDL particles, BHK-ABCA1, BHK-ABCA1(W590S), and BHK-ABCA1(C1477R) cells were plated at the same density, labeled with [3 H]cholesterol, induced to express ABCA1 at the maximum level, and exposed to a high concentration of human lipid-free apoAI, followed by the regular procedure to collect and analyze nascent HDL via gel filtration. Login to comment
168 The total amount of newly generated nascent HDL, the [3 H]cholesterol large/small particle ratio, and the size of the larger particles were all the lowest for the C1477R mutant, intermediate for the W509S variant, and the highest for the wild-type ABCA1 (Fig. 7). Login to comment
194 BHK cells expressing wild-type ABCA1, ABCA1(W590S), or ABCA1(C1477R) were plated at the same density, labeled with [3 H]cholesterol, treated with 10 nM mifepristone, and exposed to 10 òe;g/ml of human apoAI to generate nascent HDL. Login to comment
195 The decreased size of gel-filtration elution peaks indicates that W590S and especially C1477R mutations dramatically reduced the ability of ABCA1 to facilitate nascent HDL assembly. Login to comment

PMID: 23559627 [PubMed] Wang S et al: "ABCA1 mediates unfolding of apolipoprotein AI N terminus on the cell surface before lipidation and release of nascent high-density lipoprotein."

No. Sentence Comment

1 One recent model from Phillips proposes that ABCA1 shuttles phospholipids from the inner to extracellular face of the plasma membrane, resulting in membrane bulges with high curvature that are sufficient to allow apoAI penetration and nHDL formation.4 Mutations in ABCA1 lead to Tangier disease and familial hypoalphalipoproteinemia, characterized by very low levels of plasma HDL-cholesterol.5 Functional studies of certain Tangier disease mutations that are properly trafficked to the plasma membrane demonstrate that ABCA1 seems to have at least 2 distinct activities6 : apoAI binding and plasma membrane remodeling, the latter demonstrated through phosphatidylserine (PS) translocation to the outer leaflet of the plasma membrane.7 The W590S mutation in the first extracellular domain of ABCA1 is defective in PS translocation, but competent for apoAI binding.5,7,8 In contrast, the C1477R mutation in the second extracellular domain of ABCA1 is defective in apoAI binding, but competent for PS translocation.7 Further demonstration of the ability of ABCA1, and the deficit of W590S isoform, to remodel the plasma membrane was provided by Nagao et al,8 who used sodium taurocholate (NaTC) as a weak detergent extracellular lipid acceptor; wild type (WT) but not W590S ABAC1 mediates increased lipid efflux to NaTC. Login to comment
4 Approach and Results-HEK293 cells were stably transfected with ABCA1 vectors, encoding wild type, and the W590S and C1477R Tangier disease mutation isoforms, along with the K939M ATP-binding domain mutant. Login to comment
6 The W590S isoform had decreased plasma membrane remodeling and lipid efflux activities, and the C1477R isoform had decreased apoAI binding, and lipid efflux activities, whereas the K939M isoform did not bind apoAI, remodel the membrane, or efflux cholesterol. Login to comment
24 HEK293 cells were stably transfected with different murine ABCA1-green fluorescent protein (GFP) fusion vectors encoding WT, K939M, W590S, and C1477R isoforms, the latter 2 identified as Tangier disease-causing mutations in the first and second large extracellular domains, respectively.6 Several clonally derived cell lines from each construction were screened by confocal fluorescence microscopy and flow cytometry to select lines for further study with equivalent ABCA1 expression. Login to comment
25 As previously described,5,9 WT, W590S, C1477R, and K939M ABCA1-GFP fusions were processed correctly in cells and expressed on the plasma membrane (Figure 1A). Login to comment
29 In contrast, the C1477R and K939M isoform-expressing cells had no significant increase in apoAI binding compared with control cells (by ANOVA posttest). Login to comment
31 We were able to take advantage of this nonspecific apoAI binding to the control and the C1477R and K939M isoform-expressing cells in cell studies described below. Login to comment
32 ABCA1 has been shown to possess PS floppase activity, resulting in plasma membrane remodeling that has been postulated to facilitate HDL assembly.7 Using flow cytometry to measure cell surface PS assayed by Cy5-AnnexinV binding, we showed that WT and C1477R-ABCA1 isoforms increased cell surface PS by ࣈ2.2-fold compared with control cells (P<0.001 by ANOVA posttest). Login to comment
34 Thus, our results confirmed previous findings by Singaraja et al5 and Nagao et al8 that the W590S mutation in ABCA1`s first extracellular domain greatly diminishes PS floppase activity indicative of a defect in plasma membrane remodeling, whereas the C1477R mutation in its second large extracellular domain abolishes apoAI binding. Login to comment
36 In the absence of any acceptor, WT ABCA1 increased basal 3 H cholesterol efflux by 32% (P<0.05 by ANOVA posttest versus HEK), which has previously been shown to be attributable to increased microparticle release.14 The C1477R-ABCA1 isoform also had increased basal cholesterol efflux activity (34% increase; P<0.05); however, efflux from the W590S-ABCA1 isoform cell line was not significantly different from the control HEK cells. Login to comment
39 A, Confocal microscopy of wild type (WT), W590S, C1477R, and K939M ABCA1-GFP isoforms shows cell surface expression. Login to comment
40 B, Similar expression levels of WT, W590S, C1477R, and K939M ABCA1-GFP cell lines shown by flow cytometry (n=3; mean&#b1;SD; different numbers above the bars show P<0.001, by ANOVA posttest). Login to comment
42 Interestingly, both Tangier disease mutations supported partial efflux to apoAI with 4.27and 4.02-fold increases above the control HEK cells for the W590S and C1477R isoforms, respectively. Login to comment
43 All 4 cell lines have significantly different efflux to apoAI (P<0.001 by ANOVA posttest), except for efflux from the W590S and C1477R cells that were not different from each other. Login to comment
47 However, the C1477R-ABCA1 isoform yielded 5.04% cholesterol efflux, more similar to the WT ABCA1 isoform. Login to comment
48 Thus, both in the absence of acceptor or in the presence of NaTC, cholesterol efflux followed PS floppase activity (highest for WT and C1477R isoforms), and we confirmed the use of NaTC acceptor as an independent indicator of ABCA1-mediated membrane remodeling. Login to comment
49 Thus, our findings show that ABCA1 mutations that disrupt either plasma membrane remodeling (W590S) or apoAI binding (C1477R) are still competent to mediate cholesterol efflux to apoAI, albeit at reduced efficiency. Login to comment
62 A, Alexa647-labeled apoAI binding to nontransfected cells (HEK) and cells stably transfected with wild type (WT), W590S, C1477R, and K939M ABCA1-green fluorescent protein (GFP) vectors assayed by flow cytometry (n=3; mean&#b1;SD; P<0.0005 for HEK in the presence or absence of labeled apoAI by t test; for the 5 cell types in the presence of labeled apoAI different numbers above the bars show P<0.001; by ANOVA posttest). Login to comment
64 C, Cholesterol efflux from control HEK cells and WT, W590S, and C1477R ABCA1-GFP transfected cells in the absence of exogenous acceptors or in the presence of 5 bc;g/mL apoAI or 2 mmol/L sodium taurocholate (NaTC; n=3; mean&#b1;SD; different numbers above the bars show P<0.05, by ANOVA posttest). Login to comment
69 Here, we took advantage of the high sensitivity of flow cytometry and our observation that even control HEK cells and cells expressing the apoAI-binding defective C1477R and K939M-ABCA1 isoforms bound apoAI nonspecifically, enabling us to determine the Bodipy-TMR/Alexa647 ratio of each cell. Login to comment
75 The other partially active C1477R isoform has 2 activities: apoAI unfolding (albeit reduced) and plasma membrane remodeling. Login to comment
113 We chose to further study 2 specific mutations in the first (W590S) and second (C1477R) extracellular domains, respectively, based on their previously identified distinct activities. Login to comment
114 Fitzgerald et al17 examined 5 Tangier disease mutations that mapped to the 2 large extracellular domains, and reported that only the W590S mutation in the first extracellular domain was still competent to mediate apoAI cross-linking, whereas other mutations in the first (R587W and Q597R) and second (C1477R and S1506L) extracellular domains could not mediate apoAI cross-linking. Login to comment
116 Our findings reproduce that the W590S isoform has plasma membrane localization and WT levels of apoAI-binding activity; and that it has partial cholesterol efflux activity to extracellular apoAI compared with the WT isoform, as previously demonstrated.5,7,8,18 We chose to study the C1477R mutation in the second extracellular domain because it is processed correctly to the plasma membrane and has defective apoAI binding,5,7,17 but it retains its PS translocase activity and partial efflux activity,7 all findings that we confirmed in the current study, where we found ࣈ50% cholesterol efflux activity to apoAI. Login to comment
118 Here, we compared the acceptor activity of NaTC for cells expressing WT, W590S, and C1477R-ABCA1 isoforms, and found that the C1477R mutant has equivalent efflux to NaTC as the WT isoform, whereas the W590S mutant has no detectable efflux to NaTC above nontransfected cells. Login to comment
119 The NaTC efflux activities of these ABCA1 isoforms is similar to the PS translocase activity, and thus both of these assays are evidence that the WT and C1477R isoforms can remodel the plasma membrane, whereas the W590S isoform is mostly deficient in this activity. Login to comment

PMID: 23687307 [PubMed] Mineo C et al: "Regulation of signal transduction by HDL."

No. Sentence Comment

152 In studies of cAMP production and ABCA1 phosphorylation mediated by the apoA-I/ABCA1 tandem, it was found that mutations of ABCA1 associated with Tangier disease (C1477R, 2203X, and 2145X) cause the attenuation of both responses (99). Login to comment

PMID: 24097981 [PubMed] Quazi F et al: "Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants."

No. Sentence Comment

65 Mutations introduced by overlap extension PCR using Pfu AD DNA polymerase in ABCA1 included S100C, W590S, F593L, N935S, T929I, C1477R, T1512M, R2081W, and P2150L. Login to comment
67 ABCA1-MM was constructed to harbor the Walker A-motif lysine-to-methionine mutations K939M/K1952M by the nested PCR method; ABCA4-MM had the corresponding K969M/ K1969M Walker A mutations (37), and ABCA7-MM had the Lipid Transport Activity of ABCA Transporters NOVEMBER 29, 2013ߦVOLUME 288ߦNUMBER 48 JOURNAL OF BIOLOGICAL CHEMISTRY 34415 at SEMMELWEIS UNIV OF MEDICINE on December 3, K847M/K1833M Walker A mutations. Login to comment
208 Expression and Purification of Disease-causing ABCA1 and ABCA4 Mutants-As part of this study, we have generated a number of disease-causing mutations in ABCA1 and ABCA4 to determine their effect on the expression and functional properties of these transporters. We focused our studies on nine missense mutations in ABCA1 known to cause Tangier disease, including three (S100C, W590S, and F593L) in ECD1, two (T929I and N935S) in the NBD1, two (C1477R and T1512M) in ECD2, one (R2081W) in NBD2, and one (P2150L) in the C-terminal segment as shown in Fig. 6A (blue). Login to comment
223 Finally, the null mutant C1502X associated with Stargardt disease was modified to C1502R to reflect the primary sequence change of the corresponding C1477R mutant in ABCA1 linked to Tangier disease. Login to comment
226 The levels of expression of the ABCA1 and ABCA4 mutants were generally lower than the corresponding WT proteins with the ABCA1 mutants S100C and R2081W and the corresponding ABCA4 mutants S100P and R2107P expressing at levels less than 25% of WT and the remaining mutants expressing in the range of 35-90% of the WT proteins. Login to comment
229 Variants in the ECD1 (S100C, W590S, and F593L), NBD1 (T929I and N935S), and NBD2 (R2081W) of ABCA1 showed significantly reduced ATPase activities in the range of 20-35% of WT activity (Fig. 7A). Login to comment
231 The C1477R mutant in ECD2 showed an intermediate reduction in activity. Login to comment
232 ABCA4 variants showed a similar ATPase activity profile as the ABCA1 mutants with the exception of the T1537M mutation of ABCA4, which was significantly lower than the corresponding T1512M mutant in ABCA1. Login to comment
234 As shown in Fig. 8, A and B, the Fl-PC flippase activity of the ABCA1 mutants and the Fl-PE flippase activity of ABCA4 mutants have a similar profile with the ABCA1 variants C1477R, T1512M, and P2150L and corresponding ABCA4 variants C1502R, T1537M, and P2180L showing transport activities ranging from 60 to 80% of the WT protein and the other mutants showing reduced activity in the range of 20-40% of the WT protein. Login to comment
251 Some disease alleles such as W590S, C1477R, and P2150L (ABCA1) have conserved residues in ABCA4, but mutations in these positions in ABCA4 have yet to be linked to Stargardt disease. Login to comment
295 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (20-30% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT). Login to comment
311 For example, the C1477R mutant shows intermediate (b03;60% WT) phospholipid transport activity, whereas it shows minimum (b0d;20% WT) phospholipid efflux activity. Login to comment
211 Expression and Purification of Disease-causing ABCA1 and ABCA4 Mutants-As part of this study, we have generated a number of disease-causing mutations in ABCA1 and ABCA4 to determine their effect on the expression and functional properties of these transporters. We focused our studies on nine missense mutations in ABCA1 known to cause Tangier disease, including three (S100C, W590S, and F593L) in ECD1, two (T929I and N935S) in the NBD1, two (C1477R and T1512M) in ECD2, one (R2081W) in NBD2, and one (P2150L) in the C-terminal segment as shown in Fig. 6A (blue). Login to comment
237 As shown in Fig. 8, A and B, the Fl-PC flippase activity of the ABCA1 mutants and the Fl-PE flippase activity of ABCA4 mutants have a similar profile with the ABCA1 variants C1477R, T1512M, and P2150L and corresponding ABCA4 variants C1502R, T1537M, and P2180L showing transport activities ranging from 60 to 80% of the WT protein and the other mutants showing reduced activity in the range of 20-40% of the WT protein. Login to comment
254 Some disease alleles such as W590S, C1477R, and P2150L (ABCA1) have conserved residues in ABCA4, but mutations in these positions in ABCA4 have yet to be linked to Stargardt disease. Login to comment
298 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (20-30% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT). Login to comment
314 For example, the C1477R mutant shows intermediate (b03;60% WT) phospholipid transport activity, whereas it shows minimum (b0d;20% WT) phospholipid efflux activity. Login to comment
64 Mutations introduced by overlap extension PCR using Pfu AD DNA polymerase in ABCA1 included S100C, W590S, F593L, N935S, T929I, C1477R, T1512M, R2081W, and P2150L. Login to comment
206 Expression and Purification of Disease-causing ABCA1 and ABCA4 Mutants-As part of this study, we have generated a number of disease-causing mutations in ABCA1 and ABCA4 to determine their effect on the expression and functional properties of these transporters. We focused our studies on nine missense mutations in ABCA1 known to cause Tangier disease, including three (S100C, W590S, and F593L) in ECD1, two (T929I and N935S) in the NBD1, two (C1477R and T1512M) in ECD2, one (R2081W) in NBD2, and one (P2150L) in the C-terminal segment as shown in Fig. 6A (blue). Login to comment
221 Finally, the null mutant C1502X associated with Stargardt disease was modified to C1502R to reflect the primary sequence change of the corresponding C1477R mutant in ABCA1 linked to Tangier disease. Login to comment
249 Some disease alleles such as W590S, C1477R, and P2150L (ABCA1) have conserved residues in ABCA4, but mutations in these positions in ABCA4 have yet to be linked to Stargardt disease. Login to comment
293 The ABCA1/ABCA4 mutants in the ECD1 (S100C/S100P, W590S/ W605S, and F593L/F608L) displayed the lowest activities (2030% WT), whereas those in the ECD2 (C1477R/C1502R and T1512M/T1537M) and the P2150L/P2180L mutants in the C terminus showed the highest activities (60-100% WT). Login to comment
309 For example, the C1477R mutant shows intermediate (b03;60% WT) phospholipid transport activity, whereas it shows minimum (b0d;20% WT) phospholipid efflux activity. Login to comment

PMID: 24220029 [PubMed] Gulshan K et al: "Sphingomyelin depletion impairs anionic phospholipid inward translocation and induces cholesterol efflux."

No. Sentence Comment

107 As previously observed (15, 24-26), cholesterol efflux to apoAI from cells expressing either the W590S (PS translocation deficient) or C1477R (apoAI binding deficient) ABCA1 mutant isoforms was partially, but not completely impaired compared with the WT isoform (p b0d; 0.001 compared with control HEK and WT ABCA1 by ANOVA post test). Login to comment
109 Thus, myriocin treatment could overcome much of the impaired cholesterol efflux activity of the W590S Abca1 mutation, although not greatly improving efflux from the C1477R mutation. Login to comment
128 Non-transfected HEK293 cells along with HEK cells transfected with WT-Abca1-GFP, W590S-Abca1-GFP, or C1477R-Abca1-GFP isoforms were incubated with radiolabeled cholesterol and subsequently chased with apoAI (5 òe;g/ml) for 6 h. Login to comment

PMID: 25127959 [PubMed] Koopal C et al: "Premature atherosclerosis, extremely low HDL-cholesterol and concurrent defects in APOA1 and ABCA1 genes: a family case report."

No. Sentence Comment

18 The mutations were an AAG (lysine) deletion in exon 4 (c.391_393deletion; p.Lys131del) of the APOA1 gene and an ABCA1 missense mutation (c.4429TNC; p.C1477R) in exon 31. Login to comment
46 5 - - CAC-score (MESA %) 3663 (99) 59 (99) - 0 (0) - - - 33 (95) 0 (0) - - 6. HDL-c 0.74 mmol/L CAC 0 9. HDL-c 1.18 mmol/L 3. HDL-c 0.65 mmol/L AAA + MI 4. HDL-c 0.65 mmol/L 5. HDL-c 1.00 mmol/L 7. HDL-c 1.12 mmol/L CAC 33 1. HDL-c <0.20 mmol/L CAC 3663, MI 2. HDL-c 0.28 mmol/L CAC 59 8. HDL-c 1.07 mmol/L CAC 0 10. HDL-c 0.92 mmol/L 11. HDL-c 1.27 mmol/L 78 yrs 77 yrs 52 yrs 51 yrs 51 yrs 49 yrs 45 yrs 43 yrs 25 yrs 22 yrs 20 yrs MI = myocardial infarction AAA = abdominal aortic aneurysm Male with APOA1 mutation (p.Lys131del) Female with ABCA1 mutation (p.C1477R) CAC = coronary artery calcium Male with ABCA1 mutation (p.C1477R) Female with APOA1 mutation (p.Lys131del) Fig. 1. Login to comment

PMID: 26073400 [PubMed] van Capelleveen JC et al: "Myocardial infarction in a 36-year-old man with combined ABCA1 and APOA-1 deficiency."

No. Sentence Comment

57 Many case studies in these patients have reported premature atherosclerosis, indicating a clear association of HDL-C deficiency with CVD risk.14,15 Although the extreme rarity of the genetic combination and possible referral bias does preclude us from drawing firm conclusions regarding the etiology of atherosclerosis in this patient, we feel that the low HDL-C and corresponding impairment in RCT is an important factor.14,15 The genetic basis of the low HDL-C in one of the recently described families with HDL-C deficiency16 was in fact, a combination of ABCA1 (p.Cys1477Arg) and APOA1 (p.Lys130del) mutations, which has also been shown to be well characterized for the impact on RCT.8,9,17 Conclusion In this report, we present a patient with extremely low HDL-C levels based on a unique combined deficiency of ABCA1 and apoA-1. Login to comment

PMID: 26173179 [PubMed] Ito A et al: "LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling."

No. Sentence Comment

81 Selected genes that are annotated with the 'Immune system process` GO Figure 2. continued on next page To further examine the function of Abca1 was critical for inflammatory repression, we reconstituted iBMDM from myeloid-specific Abca1-/- mice with wild-type Abca1 or two different Abca1 point mutants that lacks cholesterol efflux ability, N935S and C1477R (Singaraja et al., 2006; Kannenberg et al., 2013). Login to comment
82 When Abca1-deficient cells were reconstituted with wild-type Abca1, inflammatory gene expression was repressed by LXR activation; however, this effect was lost in cells expressing the N935S or C1477R mutants (Figure 4C). Login to comment