ABCMdb

ABCA1 p.Leu1056Pro

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Publications

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
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
181 The HDL from the ABCA1 homozygote for mutation p.L1056P was extremely low and could not be tested for its antioxidant/anti-inflammatory properties by the DCF assay. 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
178 The HDL from the ABCA1 homozygote for mutation p.L1056P was extremely low and could not be tested for its antioxidant/anti-inflammatory properties by the DCF assay. 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

61 Eight novel missense variations [c.299C > G (p.S100C), c.1724A > G (p.D575G), c.1779C > G (p.F593L), c.3167T > C (p.L1056P), c.3757G > A (p.E1253K), c.4535C > T (p.T1512M), c.5573T > C (p.V1858A), c.5821T > C (p.C1941R)] were introduced into this chimeric construct by site-directed mutagenesis using Stratagene QuikChange XL site-directed mutagenesis kit according to manufacturer`s instructions (La Jolla, CA, USA). Login to 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
94 From eight novel missense variations identified in our cohort, one is localized in the first transmembrane domain (p.S100C), two in the first large extracellular loop (p.D575G and p.F593L), two in the first Nuclear Binding Domain (p.L1056P and p.E1253K), one in the second large extracellular loop (p.T1512M), one in the extracellular region, close to the plasma membrane (p.V1858A) and one is localized in the C-terminal domain (p.C1941R). Login to comment
98 Four out of eight mutations were predicted to be probably damaging (p.S100C, p.D575G, p.T1512M, p.C1941R), two as possibly damaging (p.F593L and p.L1056P) and two were described as benign (p.E1253K and p.V1858A) by PolyPhen. Login to comment
110 Fig. 2 shows that the ABCA1-p.S100C, p.D575G, p.F593L, p.L1056P, p.E1253K, p.T1512M, p.C1941R mutant proteins all had a significantly reduced capacity to efflux cholesterol to apo A-I compared to wild-type ABCA1 which is in line with the low HDL cholesterol levels of the individuals in whom the mutations were identified. Login to comment
136 The most striking discrepancy was found for the new ABCA1-p.L1056P variant which was only defined as possibly damaging while our data show that this variant is amongst those with the most profound loss of ABCA1-mediated efflux and confocal microscopy revealed complete intracellular retention (Supplementary Fig. 1). Login to comment
143 The missense mutations ABCA1-p.L1056P and ABCA1-p.E1253K, identified in patients with near HDL deficiency, are located in the intracellular region, inside the nuclear binding domain 1, close to the Walker A motif and after the Walker B motif respectively (Fig. 1). Login to comment
146 Thus, lack of proper localization to the plasma membrane for ABCA1-p.L1056P and partial intracellular retention for ABCA1-p.E1253K (Supplementary Fig. 1) results in low cholesterol efflux potential of both ABCA1 mutants and confirms the vital role of this ABCA1 domain (Fig. 2). 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

69 Subjects were carriers of the following mutations: c.6401+2T.C, p.Ser930Phe, p.Ser824Leu, p.Arg587Trp, p.Thr929Ile, p.Asn935Ser, c.3535+1G.C, p.Asp571Gly, p.Asn1800his, p.Leu1056Pro, p.Gln1038Ter, c.1195-1G.C, p.Arg579Gln, and p.Phe1760Valfs*21. Login to comment
78 Five of these mutations have already been shown to have a significant impact on ABCA1 function (p.Asn1800his,27 p.Thr929Ile,27 p.Arg587Trp,28,29 p.Leu1056Pro,21 and p.Phe1760Valfs*21.30 ). Login to comment

PMID: 26109739 [PubMed] Bochem AE et al: "Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins."

No. Sentence Comment

28 Homozygous and compoundheterozygoussubjectshadTangierDisease.Subjects were carriers of the following mutations: p.Leu1056Pro, c.3535+1G>C, c.6401+2T>C, p.Asn1800his, p.Ser930Phe, p.Phe1760Valfs*21, p.Ser824Leu, p.Gln1038Ter, p.Thr929Ile, p.Arg587Trp, p.Asn935Ser, and p.Arg579Gln. Login to comment