ABCMdb

ABCA1 p.Val1858Ala

None has been submitted yet.

Publications

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
99 Using SIFT, seven novel variations were predicted to affect protein function, while one (p.V1858A) was predicted to be tolerated. Login to comment
111 The ABCA1-p.V1858A, however, had a normal potential to efflux cholesterol to apo A-I which is in line with the prediction that the mutation is benign (both PolyPhen and SIFT) suggesting that the low HDL cholesterol in this individual is likely the result of other, yet unknown molecular defect. Login to comment
114 While WT-ABCA1 and ABCA1-V1858A variant show normal localization on plasma membrane, ABCA1- L1056 protein shows a complete intracellular retention. Login to comment
138 In contrast to PolyPhen, SIFT predictions for the assessment of the novel variations studied here were more compatible to the outcome of our in vitro experiments, i.e. all variants with significant reduction in cholesterol efflux to apo A-I in our in vitro assay were proposed to be deleterious while ABCA1-p.V1858A was predicted to be tolerated. Login to comment
157 The ABCA1-p.V1858A variant was the only missense variation that was found to have no significant effect on cholesterol efflux and cellular localization. Login to comment