ABCMdb

ABCA1 p.His551Asp

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Publications

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

No. Sentence Comment

45 Previous studies demonstrated the importance of the C-terminal region for the functional activity of PLTP and the arginine at position 459 is within the C-terminus.31 PLTP expression in COS7 cells showed that PLTP mutants S107Y and R459Q had normal and 33% decrease in specific activity relative to wild-type protein, respectively (115.3Ϯ11.2, 66.7Ϯ6.0 of wild-type activity). Login to 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
49 Eight subjects with sequence variants in ABCA1 had defective cholesterol efflux (measured in repeated assays cholesterol-loaded monocyte-derived macrophage [MDMs]), and these ABCA1 sequence variants were tested in an in vitro expression system for cholesterol efflux activity.38 ABCA1 proteins containing the sequence variants W590L, C1477F, D1706N, S1731C, or N1800H were all found to have significantly impaired cholesterol efflux, whereas the H551D and E1386Q variants had very minor, if any, effects on cholesterol transport (Figure 1A). Login to comment
50 The H551D variant had close to normal efflux capacity but reduced cell surface presentation (Figure 1B), thereby affecting activity. Login to comment
75 All mutants were found to have significantly impaired cholesterol efflux, with the exception of E1386Q and H551D. Login to comment
80 The H551D mutant had significantly decreased cell surface presentation. Login to comment
88 of Subjects Functional Mutations (All Heterozygous) Percentage of Total Population ApoA-I 2 33X, ⌬K182 2 ABCA1 7 H551D, W590L, C1477F, D1706N, S1731C, N1800H, 1851X 6 LCAT 4 W61X, G104S, N131D, S208T 3 PLTP 1 R459Q 1 Unknown 88 Total no. Login to comment
103 As a positive control, we recruited first-degree relatives of a group B subject possessing a novel ABCA1 mutation, H551D. Login to comment
141 Future studies will focus on the HDL 0.68 mM <5th% Efflux 0.31% HDL 1.25 mM 40th% Efflux 0.53% HDL 0.90 mM <5th% Efflux 0.28% HDL 0.85 mM <5th% Efflux 0.29% HDL 1.54 mM 70th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.33% HDL 1.38 mM 50th% Efflux 0.56% HDL 0.90 mM 20th% Efflux 0.41% HDL 0.75 mM <5th% Efflux 0.21% HDL 0.91 mM 20th% Efflux 0.46% HDL 0.62 mM <5th% Efflux 0.35% HDL 1.40 mM 80th% Efflux 0.45% HDL 1.60 mM 90th% Efflux 0.58% HDL 0.72 mM <5th% Efflux 0.29% HDL 1.70 mM 75th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.20% HDL 0.69 mM <5th% Efflux 0.38% HDL 0.78 mM <5th% Efflux 0.30% HDL 1.62 mM 75th% Efflux 0.55% Heritability of efflux defects Group B: H551D mut. Login to comment
145 The proband and 2 children in the family depicted in the top left pedigree are carriers of a H551D mutation in ABCA1, demonstrating cosegregation of this mutation with a cholesterol efflux defect and low HDL. 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
44 Eight subjects with sequence variants in ABCA1 had defective cholesterol efflux (measured in repeated assays cholesterol-loaded monocyte-derived macrophage [MDMs]), and these ABCA1 sequence variants were tested in an in vitro expression system for cholesterol efflux activity.38 ABCA1 proteins containing the sequence variants W590L, C1477F, D1706N, S1731C, or N1800H were all found to have significantly impaired cholesterol efflux, whereas the H551D and E1386Q variants had very minor, if any, effects on cholesterol transport (Figure 1A). Login to comment
70 All mutants were found to have significantly impaired cholesterol efflux, with the exception of E1386Q and H551D. Login to comment
83 of Subjects Functional Mutations (All Heterozygous) Percentage of Total Population ApoA-I 2 33X, èc;K182 2 ABCA1 7 H551D, W590L, C1477F, D1706N, S1731C, N1800H, 1851X 6 LCAT 4 W61X, G104S, N131D, S208T 3 PLTP 1 R459Q 1 Unknown 88 Total no. Login to comment
98 As a positive control, we recruited first-degree relatives of a group B subject possessing a novel ABCA1 mutation, H551D. Login to comment
136 Future studies will focus on the HDL 0.68 mM <5th% Efflux 0.31% HDL 1.25 mM 40th% Efflux 0.53% HDL 0.90 mM <5th% Efflux 0.28% HDL 0.85 mM <5th% Efflux 0.29% HDL 1.54 mM 70th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.33% HDL 1.38 mM 50th% Efflux 0.56% HDL 0.90 mM 20th% Efflux 0.41% HDL 0.75 mM <5th% Efflux 0.21% HDL 0.91 mM 20th% Efflux 0.46% HDL 0.62 mM <5th% Efflux 0.35% HDL 1.40 mM 80th% Efflux 0.45% HDL 1.60 mM 90th% Efflux 0.58% HDL 0.72 mM <5th% Efflux 0.29% HDL 1.70 mM 75th% Efflux 0.49% HDL 0.60 mM <5th% Efflux 0.20% HDL 0.69 mM <5th% Efflux 0.38% HDL 0.78 mM <5th% Efflux 0.30% HDL 1.62 mM 75th% Efflux 0.55% Heritability of efflux defects Group B: H551D mut. Login to comment
140 The proband and 2 children in the family depicted in the top left pedigree are carriers of a H551D mutation in ABCA1, demonstrating cosegregation of this mutation with a cholesterol efflux defect and low HDL. 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

110 DOI: 10.1371/journal.pgen.0010083.g003 Table 3. subPSEC Scores for ABCA1 Variants Described in a Cohort of Individuals with Low HDL Cholesterol from the General Population Variant subPSEC Score Macrophage Efflux PolyPhen D1706N À6.57 0.38a Possibly damaging C1477F À5.55 0.34a Probably damaging W590S À5.19 - Probably damaging H551D À4.99 0.32a Probably damaging P85L À4.62 0.8 Probably damaging W590L À4.48 0.31a Probably damaging N1800H À4.23 0.27a Possibly damaging R965C À4.22 0.59 Probably damaging S1731C À4.21 0.28a Possibly damaging A1670T À4.2 - Possibly damaging K401Q À4.2 - Benign T459P À4.11 0.28a Possibly damaging R638Q À4.08 - Possibly damaging L1026P À3.86 0.25a Benign T2073A À3.84 0.28a Possibly damaging E815G À3.53 - Probably damaging R1615Q À3.45 - Possibly damaging S1181F À3.44 - Possibly damaging R306H À3.31 - Benign E1386Q À2.44 0.51 Benign S1376G À2.19 - Benign R1341T À2.09 - Possibly damaging D2243E À1.6 - Benign P248A À0.18 - Benign a Efflux value is 2 SDs or more below control levels of 0.52 6 0.07. Login to comment