ABCA1 p.Leu1056Pro
| Predicted by SNAP2: | A: D (80%), C: D (53%), D: D (95%), E: D (91%), F: D (85%), G: D (91%), H: D (91%), I: D (71%), K: D (95%), M: D (53%), N: D (91%), P: D (91%), Q: D (91%), R: D (91%), S: D (91%), T: D (91%), V: D (75%), W: D (80%), Y: D (91%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Characterization of antioxidant/anti-inflammatory ... Clin Chim Acta. 2011 Jun 11;412(13-14):1213-20. Epub 2011 Mar 21. Daniil G, Phedonos AA, Holleboom AG, Motazacker MM, Argyri L, Kuivenhoven JA, Chroni A
Characterization of antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations of HDL from family subjects with monogenic low HDL disorders.
Clin Chim Acta. 2011 Jun 11;412(13-14):1213-20. Epub 2011 Mar 21., [PMID:21420943]
Abstract [show]
BACKGROUND: Genetic factors regulate both high-density lipoprotein (HDL) levels and functionality, thus affecting HDL antiatherogenic properties. We characterized the HDL antioxidant/anti-inflammatory properties and apoA-I-containing subpopulations in families with monogenic low HDL disorders. METHODS: Subjects with mutations in apolipoprotein A-I (apoA-I), ATP-binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT) and family controls were studied. HDL antioxidant/anti-inflammatory properties were assayed by an in vitro fluorometric method and HDL-associated paraoxonase-1 (PON1), platelet activating factor-acetylhydrolase (PAF-AH), LCAT, malondialdehyde (MDA), PAF and serum amyloid A (SAA) were measured. ApoA-I-containing HDL subpopulations were analyzed by two-dimensional non-denaturing gel electrophoresis. RESULTS: ApoA-I heterozygotes and subjects with partial or complete ABCA1 or LCAT deficiency had HDL with reduced antioxidant/anti-inflammatory properties and increased MDA levels. HDL-PON1 activity was reduced in apoA-I heterozygotes and in subjects with complete ABCA1 deficiency. HDL-PAF-AH activity was reduced in subjects with partial or complete ABCA1 deficiency or complete LCAT deficiency. HDL-LCAT activity was reduced in all LCAT mutation carriers. HDL-PAF levels were increased in apoA-I heterozygotes. HDL-SAA levels were increased in subjects with complete ABCA1 deficiency. ApoA-I, ABCA1 and LCAT heterozygotes were depleted of the large alpha1 HDL subpopulation. Subjects with complete LCAT deficiency showed mostly the small alpha4 HDL subpopulation and subjects with complete ABCA1 deficiency the alpha4 and prebeta HDL subpopulations. CONCLUSIONS: This study shows that mutations in apoA-I, ABCA1 and LCAT have direct effect on the antioxidant/anti-inflammatory properties of HDL. Furthermore, our study shows the effect of specific mutations on the apoA-I-containing HDL subpopulation profiles.
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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.
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ABCA1 p.Leu1056Pro 21420943:56:353
status: NEW162 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).
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ABCA1 p.Leu1056Pro 21420943:162:56
status: NEW163 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].
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ABCA1 p.Leu1056Pro 21420943:163:91
status: NEWX
ABCA1 p.Leu1056Pro 21420943:163:98
status: NEW164 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).
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ABCA1 p.Leu1056Pro 21420943:164:271
status: NEW166 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.
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ABCA1 p.Leu1056Pro 21420943:166:91
status: NEWX
ABCA1 p.Leu1056Pro 21420943:166:98
status: NEW176 p.C1477R/ IVS25+1GNC and a homozygote for ABCA1 mutation p.L1056P presented with CAD [24,25].
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ABCA1 p.Leu1056Pro 21420943:176:59
status: NEW181 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.
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ABCA1 p.Leu1056Pro 21420943:181:49
status: NEW159 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).
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ABCA1 p.Leu1056Pro 21420943:159:56
status: NEW160 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].
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ABCA1 p.Leu1056Pro 21420943:160:104
status: NEW161 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).
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ABCA1 p.Leu1056Pro 21420943:161:271
status: NEW173 p.C1477R/ IVS25+1GNC and a homozygote for ABCA1 mutation p.L1056P presented with CAD [24,25].
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ABCA1 p.Leu1056Pro 21420943:173:59
status: NEW178 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.
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ABCA1 p.Leu1056Pro 21420943:178:49
status: NEW[hide] Plasma levels of 27-hydroxycholesterol in humans a... Atherosclerosis. 2011 Feb;214(2):448-55. Epub 2010 Nov 3. Karuna R, Holleboom AG, Motazacker MM, Kuivenhoven JA, Frikke-Schmidt R, Tybjaerg-Hansen A, Georgopoulos S, van Eck M, van Berkel TJ, von Eckardstein A, Rentsch KM
Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.
Atherosclerosis. 2011 Feb;214(2):448-55. Epub 2010 Nov 3., [PMID:21130455]
Abstract [show]
Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol. Compared to family controls and relative to the concentrations of total 27OHC and cholesterol, lower 27OHC-ester but normal cholesterylester levels were found in HDL of heterozygous LCAT mutation carriers and nonHDL of heterozygous CETP mutation carriers. In family controls, LCAT activity and CETP mass were more strongly correlated with 27OHC-ester than cholesterylester concentrations in HDL and nonHDL, respectively. These findings suggest that the formation and transfer of 27OHC-esters are more sensitive to reduced activities of LCAT and CETP, respectively, than the formation and transfer of cholesterylesters. 27OHC plasma levels were also decreased in apoA-I-, ABCA1- or LCAT-knockout mice but increased in SR-BI-knockout mice. Transplantation of ABCA1- and/or ABCG1-deficient bone marrow into LDL receptor deficient mice decreased plasma levels of 27OHC. In conclusion, mutations or absence of HDL genes lead to distinct alterations in the quantity, esterification or lipoprotein distribution of 27OHC. These findings argue against the earlier suggestion that 27OHC-metabolism in plasma occurs independently of HDL.
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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.
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ABCA1 p.Leu1056Pro 21130455:63:458
status: NEWX
ABCA1 p.Leu1056Pro 21130455:63:592
status: NEW62 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.
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ABCA1 p.Leu1056Pro 21130455:62:443
status: NEWX
ABCA1 p.Leu1056Pro 21130455:62:572
status: NEW[hide] Identification and characterization of novel loss ... Atherosclerosis. 2010 Dec;213(2):492-8. Epub 2010 Aug 26. Candini C, Schimmel AW, Peter J, Bochem AE, Holleboom AG, Vergeer M, Dullaart RP, Dallinga-Thie GM, Hovingh GK, Khoo KL, Fasano T, Bocchi L, Calandra S, Kuivenhoven JA, Motazacker MM
Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.
Atherosclerosis. 2010 Dec;213(2):492-8. Epub 2010 Aug 26., [PMID:20880529]
Abstract [show]
OBJECTIVES: The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. METHODS: The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells. RESULTS: Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. CONCLUSION: This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.
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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).
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ABCA1 p.Leu1056Pro 20880529:61:116
status: NEW76 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.
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ABCA1 p.Leu1056Pro 20880529:76:175
status: NEW89 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).
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ABCA1 p.Leu1056Pro 20880529:89:276
status: NEW94 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).
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ABCA1 p.Leu1056Pro 20880529:94:233
status: NEW98 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.
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ABCA1 p.Leu1056Pro 20880529:98:147
status: NEW110 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.
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ABCA1 p.Leu1056Pro 20880529:110:57
status: NEW136 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).
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ABCA1 p.Leu1056Pro 20880529:136:60
status: NEW143 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).
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ABCA1 p.Leu1056Pro 20880529:143:31
status: NEW146 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).
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ABCA1 p.Leu1056Pro 20880529:146:69
status: NEW[hide] ABCA1 mutation carriers with low high-density lipo... Eur Heart J. 2013 Jan;34(4):286-91. doi: 10.1093/eurheartj/ehs376. Epub 2012 Nov 7. Bochem AE, van Wijk DF, Holleboom AG, Duivenvoorden R, Motazacker MM, Dallinga-Thie GM, de Groot E, Kastelein JJ, Nederveen AJ, Hovingh GK, Stroes ES
ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden.
Eur Heart J. 2013 Jan;34(4):286-91. doi: 10.1093/eurheartj/ehs376. Epub 2012 Nov 7., [PMID:23136402]
Abstract [show]
AIMS: Low HDL-C is a potent risk factor for cardiovascular disease (CVD). Yet, mutations in ABCA1, a major determinant of circulating HDL-C levels, were previously not associated with CVD risk in cohort studies. To study the consequences of low plasma levels of high-density lipoprotein cholesterol (HDL-C) due to ATP-binding cassette transporter A1 (ABCA1) dysfunction for atherosclerotic vascular disease in the carotid arteries. METHODS AND RESULTS: We performed 3.0 Tesla magnetic resonance imaging (MRI) measurements of the carotid arteries in 36 carriers of high impact functional ABCA1 mutations and 36 normolipidemic controls. Carriers presented with 42% lower HDL-C levels (P < 0.001), a larger mean wall area (18.6 +/- 6.0 vs. 15.8 +/- 4.3 mm(2); P = 0.02), a larger mean wall thickness (0.82 +/- 0.21 vs. 0.70 +/- 0.14 mm; P = 0.005), and a higher normalized wall index (0.37 +/- 0.06 vs. 0.33 +/- 0.04; P = 0.005) compared with controls, retaining significance after adjustment for smoking, alcohol consumption, systolic blood pressure, diabetes, body mass index, history of CVD, LDL-C, and statin use (P = 0.002). CONCLUSION: Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.
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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.
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ABCA1 p.Leu1056Pro 23136402:69:171
status: NEW78 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 ).
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ABCA1 p.Leu1056Pro 23136402:78:147
status: NEW[hide] Increased Systemic and Plaque Inflammation in ABCA... Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1663-9. doi: 10.1161/ATVBAHA.114.304959. Epub 2015 Feb 19. Bochem AE, van der Valk FM, Tolani S, Stroes ES, Westerterp M, Tall AR
Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins.
Arterioscler Thromb Vasc Biol. 2015 Jul;35(7):1663-9. doi: 10.1161/ATVBAHA.114.304959. Epub 2015 Feb 19., [PMID:26109739]
Abstract [show]
OBJECTIVE: We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans. APPROACH AND RESULTS: Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. (18)Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P=0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P=0.03). We then measured plasma cytokine levels. Tumor necrosis factor alpha, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFalpha mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression. CONCLUSIONS: Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography-MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins.
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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.
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ABCA1 p.Leu1056Pro 26109739:28:114
status: NEW