ABCMdb

ABCA1 p.Val2244Ile

Predicted by SNAP2:	A: N (93%), C: N (87%), D: N (78%), E: N (93%), F: N (82%), G: N (72%), H: N (78%), I: N (97%), K: N (87%), L: N (93%), M: N (93%), N: N (87%), P: N (87%), Q: N (87%), R: N (78%), S: N (93%), T: N (97%), W: N (72%), Y: N (82%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: N, Y: N,

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Publications
[hide] Increased risk of coronary artery disease in Cauca... Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19. Tietjen I, Hovingh GK, Singaraja R, Radomski C, McEwen J, Chan E, Mattice M, Legendre A, Kastelein JJ, Hayden MR
Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.
Biochim Biophys Acta. 2012 Mar;1821(3):416-24. doi: 10.1016/j.bbalip.2011.08.006. Epub 2011 Aug 19., [PMID:21875686]

Abstract [show]
Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc <10th percentile but no other major lipid abnormalities, including 89 with >/=1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p=2.44 *10(-5)). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc <10th percentile. Furthermore, only mutation carriers with HDLc <5th percentile had elevated risk of CAD (odds ratio (OR)=2.26 for 34 ABCA1 mutation carriers vs. 149 total first-degree relative controls, p=0.05; OR=2.50 for 26 APOA1 mutation carriers, p=0.04; OR=3.44 for 38 LCAT mutation carriers, p=1.1 *10(-3)). These observations show that mutations in ABCA1, APOA1, and LCAT are sufficient to explain >40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

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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

[hide] Screening for functional sequence variations and m... Atherosclerosis. 2004 Aug;175(2):269-79. Probst MC, Thumann H, Aslanidis C, Langmann T, Buechler C, Patsch W, Baralle FE, Dallinga-Thie GM, Geisel J, Keller C, Menys VC, Schmitz G
Screening for functional sequence variations and mutations in ABCA1.
Atherosclerosis. 2004 Aug;175(2):269-79., [PMID:15262183]

Abstract [show]
Mutations in the ATP-binding cassette 1 transporter gene (ABCA1) are responsible for the genetic HDL-deficiency syndromes, which are characterized by severely diminished plasma HDL-C levels and a predisposition to cardiovascular disease and splenomegaly. The ABCA1 gene contains 50 exons and codes for a 2261-amino acid long membrane protein that facilitates phospholipid and cholesterol transport. Several mutations have been identified so far as responsible either for Tangier disease or for reduced HDL levels. We have selectively looked for additional polymorphisms in functionally relevant regions of the gene in cohorts constituted of individuals with altered HDL levels as well as healthy blood donors and octogenarians, and screened for mutations in the complete coding region of selected individuals with extremely aberrant HDL levels. In the promoter region, which is important for regulation of gene expression, we have identified several polymorphisms including one VNTR polymorphism, located at a putative ZNF202 binding site, which displayed different binding of ZNF202 in an electromobility shift assay. Three novel SNPs were discovered in the promoter region (G1047C, C1152T and C1440T). The prevalence of exchange G1047C (G-395C) was found significantly increased in probands with low HDL compared to probands with high HDL. Exchanges C1152T (C-290T) and C1440T (C-7T) were significantly more frequent in the cohort with low HDL compared to healthy blood donors and octogenarians. In the C-terminal part of ABCA1, known to interact with other proteins, two novel sequence variations (F2163S and V2244I) have been found in one phenotype related to cardiovascular disease, but none in the aforementioned cohorts. In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). To facilitate further research in ABCA1 sequence variations and expand our understanding of their effects, we are introducing a webpage archive (http://www.abca1-mutants.all.at) containing all sequence variations reported in ABCA1 so far. This webpage provides a more recent and detailed summary of sequence variations and mutations in ABCA1 than existing databases and should also be of interest for molecular diagnosis of ABCA1-related HDL deficiency.

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Sentences [show]
No. Sentence Comment
8 In the C-terminal part of ABCA1, known to interact with other proteins, two novel sequence variations (F2163S and V2244I) have been found in one phenotype related to cardiovascular disease, but none in the aforementioned cohorts. Login to comment
123 These Table 1 Primers and probes for TaqMan analysis of novel polymorphisms in the coding region of ABCA1 W590L (G2082C) TM-W590L-f 5 -AGC TGA CCC CTT TGA GGA CAT-3 TM-W590L-r 5 -CTC CAC CAC ATC CTG CAA GTA G-3 TM-W590-vic 5 -VIC-CCC CCC ¯ AGA CGT A-MGB-NFQ-3 TM-L590-fam 5 -FAM-CCC CCG ¯ AGA CGT A-MGB-NFQ-3 V771M (G2624A) TM-V771M-f 5 -GGC ATC ATC TAC TTC ACG CTG TA-3 TM-V771M-r 5 -CAG AGG TAC TCA CAG CGA AGA TCT T-3 TM-V771-vic 5 -FAM-TGT GAA GCC CAC ¯ GTA G-MGB-NFQ-3 TM-M771-fam 5 -VIC-TGA AGC CCA T ¯ GT AGT C-MGB-NFQ-3 W840R (T2831A) TM-W840R-f 5 -GCT GTT TGA CAC CTT CCT CTA TGG-3 TM-W840R-r 5 -TGT ACC TGG AAA GAC AGC CTC AA-3 TM-W840-vic 5 -VIC-TGT ACC A ¯ GG TCA TCA C-MGB-NFQ-3 TM-R840-fam 5 -FAM-TGT ACC T ¯ GG TCA TCA C-MGB-NFQ-3 P2150L (C6762T) TM-P2150L-f 5 -TTC AGG TTT GGA GAT GGT TAT ACA ATA G-3 TM-P2150L-r 5 -GAA ATG CAA GTC CAA AGA AAT CCT-3 TM-P2150-vic 5 -VIC-CAA CCC ¯ GGA CCT GA-MGB-NFQ-3 TM-L2150-fam 5 -FAM-CAA CCT ¯ GGA CCT GAA-MGB-NFQ-3 F2163S (T6801C) TM-F2163S-f 5 -AAG CCT GTC CAG GAT TTC TTT G-3 TM-F2163S-r 5 -CAT GTT CCG GTG TTT CTC TTT TAG-3 TM-F2163-vic 5 -VIC-CCA GGA A ¯ AT GCA AGT C-MGB-NFQ-3 TM-S2163-fam 5 -FAM-CAG GAG ¯ ATG CAA GTC-MGB-NFQ-3 V2244I (G7043A) TM-V2244I-f 5 -ATG ATG ACC ACT TAA AAG ACC TCT CA-3 TM-V2244I-r 5 -GCT TTC TTT CAC TTT CTC ATC CTG TAG-3 TM-V2244-vic 5 -VIC-TGG ACG ¯ TTG CAG TTC-MGB-NFQ-3 TM-I2244-fam 5 -FAM-AGT AGT GGA CA ¯ T TGC-MGB-NFQ-3 Positions of sequence variations refer to accession number NM005502. Login to comment
192 In addition, patient D was heterozygous for a novel sequence variation in exon 22, Table 5 Sequence variations found in ABCA1 and phenotypes of patients Exon Amino acid Nucleotide Position in DNA (AF275948) Position in mRNA (NM005502) Found in patient with 14 W590L TG ¯ G → TC ¯ G 98481 2082 HDL deficiency (C) 16 V771M G ¯ TG → A ¯ TG 102555 2624 Increased HDL (A) 17 W840R T ¯ GG → A ¯ GG 103822 2831 HDL deficiency (B) 22 R1068C C ¯ GC → T ¯ GC 109904 3515 HDL deficiency (D) 49 F2163S TT ¯ T → TC ¯ T 143483 6801 Low HDL and G6PD deficiency (E) 50 V2244I G ¯ TT → A ¯ TT 144665 7043 A C ABC B S A N ABC B S 44 23 703 681 718 740 769 747 774-794 822 842 1368 1346 1655 1677 1724 1702 1737 1759 1790 1768 1848 1870 642 660 W590L R1068C F2163S P2150L V2244I V771M W840R Fig. 4. Login to comment
202 Several sequence variations were identified, with two of them located within exon 49 (F2163S) and exon 50 (V2244I) near the COOH-terminus of ABCA1. Login to comment
203 Analysis of the rest of the family focusing on the identified polymorphisms revealed that the mother is heterozygous for F2163S and the father is heterozygous for V2244I. Login to comment
230 However, the sequence variations found in patient E with G6PD deficiency (F2163S, V2244I) are located in exons 49 and 50, respectively, and these mutations may account for the low-HDL cholesterol. Login to comment
232 The coincidence of polymorphisms within exon 50 (V2244I) of the carboxyterminus of the ABCA1 gene and clinical correlates of succinate dehydrogenase deficiency and hypertrophic cardiomyophathy and skeletal muscle myopathy in the father (pedigree C, Fig. 1) without mutations in the G6PD gene indicates that the mutation in exon 50 of ABCA1 is causally related to dysfunctions of succinate dehydrogenase and/or G6PD, perhaps by interfering with correct protein-protein interactions and failure of shuttling between ABCA1 and the inner mitochondrial membrane. Login to comment