ABCMdb

PMID: 15262183

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., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCA1 p.Val2244Ile ABCA1 p.Phe2163Ser 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 9 ABCA1 p.Val771Met In one individual with extremely high HDL levels, the V771M polymorphism was found in a homozygous state. Login to comment 10 ABCA1 p.Arg1068Cys ABCA1 p.Trp840Arg ABCA1 p.Trp590Leu In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). Login to comment 59 ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Arg1068Cys ABCA1 p.Arg1068Cys 19 years 30 years 53 years Chol TG LDL HDL Lp(a) 116 59 82 30 <5.9 Apo E3/E4 GOT 23U/L, GPT 20 U/L, bilirubine (tot.) 1.16 Chol TG LDL HDL Lp(a) 153 94 112 27 22.7 Apo E3/E3 Chol TG LDL HDL Lp(a) 131 50 88 40 10.9 ApoE2/E3 60 years Chol TG LDL HDL Lp(a) 161 107 91 60 <5.9 ApoE3/E4 (TC ∆ ) Exon 23 G6PD deficiency R1068C I-1 I-1 I-2 I-2 dec. 67 years II-1 II-1 II-2 II-2 40 years 31 years 70 years Chol TG LDL HDL ApoAI 309 59 228 70 170 Chol TG LDL HDL ApoAI 283 145 175 54 156 Chol TG LDL HDL ApoAI 304 48 168 125 244 n.d. 60 years 32 years 23 years Chol TG LDL HDL ApoAI 237 100 121 48 110 Chol TG LDL HDL ApoAI 316 24 2 5 Chol TG LDL HDL ApoAI 158 74 109 33 86 68 years Chol TG LDL HDL ApoAI 121 191 33 87 96 49 I-1 I-2 II-1 II-2 V771M (patient A) (patient D) (patient E) A D E Fig. 1. Login to comment 123 ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Trp590Leu ABCA1 p.Trp590Leu ABCA1 p.Trp590Leu ABCA1 p.Trp590Leu ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser 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 171 ABCA1 p.Pro2150Leu Sequencing of 63 healthy octogenarians, 62 healthy blood donors, 62 individuals with low HDL and 62 individuals with high HDL revealed only one sequence variation, resulting in amino acid exchange P2150L (C143444T) which has been reported earlier by Clee et al. [1]. Login to comment 181 ABCA1 p.Val771Met Table 4 Frequencies of VNTR-SRY in various study groups and mean HDL levels (males only) DONORS High-HDL Low-HDL Total Individuals 50 33 44 221 HDL-C 57 ± 12 93 ± 16 35 ± 7 59 ± 25 Homozygotes wt (%) 2.0 12.1 6.8 6.3 (GTTT) (%) 8.0 3.0 2.3 4.7 (GTTTTGTTT) (%) 18.0 21.2 29.5 22.8 Heterozygotes wt/ (GTTT) (%) 12.0 15.2 11.4 12.6 wt/ (GTTTTGTTT) (%) 24.0 15.2 15.9 18.9 (GTTT)/ (GTTTTGTTT) (%) 34.0 33.3 34.1 33.9 Allele frequencies wt (%) 20.0 27.3 20.5 22.0 (GTTT) (%) 32.0 27.3 25.0 28.3 (GTTTTGTTT) (%) 47.0 45.5 54.5 49.2 P(χ2) - 0.541 0.516 In patient A (individual II-1 in pedigree A, Fig. 1) we identified a G102555A (V771M) polymorphism in a homozygous state. Login to comment 183 ABCA1 p.Val771Met The V771M polymorphism was analyzed in the DONORS cohort. Login to comment 184 ABCA1 p.Asn935Ser ABCA1 p.Trp840Arg We found that 451 (94.4%) out of 478 successfully genotyped individuals were wild-types, only 27 (5.6%) were heterozygous V/M771 and no homozygous M771 individual was found. Sequencing of the complete ABCA1 gene of the 50-year-old female with 2 mg/dl HDL (patient B) showed that she was heterozygous for A107009G (N935S), a known Tangier mutation [7], and also heterozygous for the novel mutation T103822A, which results in the amino acid exchange W840R. Login to comment 186 ABCA1 p.Trp590Leu In the 61-year-old male (patient C), we found the novel mutation G98481T in a heterozygous state, which results in amino acid exchange W590L. Login to comment 187 ABCA1 p.Trp590Ser A mutation in the same codon (W590S) has already been described in a Tangier patient previously analyzed in our laboratory [7]. Login to comment 188 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The patient was also heterozygous for two known polymorphisms (R219K and I883M), but no second mutation could be identified so far. Login to comment 192 ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val2244Ile ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Arg1068Cys ABCA1 p.Arg1068Cys ABCA1 p.Arg1068Cys ABCA1 p.Arg1068Cys ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Trp840Arg ABCA1 p.Pro2150Leu ABCA1 p.Pro2150Leu ABCA1 p.Trp590Leu ABCA1 p.Trp590Leu ABCA1 p.Trp590Leu ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser ABCA1 p.Phe2163Ser 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 196 ABCA1 p.Arg1068Cys ABCA1 p.Arg1068Cys which results in the amino acid exchange arginine to cysteine at codon 1068 (R1068C). Login to comment 197 ABCA1 p.Arg219Lys ABCA1 p.Glu1172Asp Three other known sequence variations have been found (heterozygous R219K, heterozygous E1172D and homozygous R1587K). Login to comment 200 ABCA1 p.Arg1068Cys The mother was found heterozygous for amino acid exchange R1068C (see pedigree D, Fig. 1). Login to comment 202 ABCA1 p.Val2244Ile ABCA1 p.Phe2163Ser 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 ABCA1 p.Val2244Ile ABCA1 p.Phe2163Ser 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 ABCA1 p.Val2244Ile ABCA1 p.Phe2163Ser 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 ABCA1 p.Val2244Ile 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 237 ABCA1 p.Val771Met In lipoprotein metabolism (cholesterol efflux) it is known that methionine oxidation in apo A-I is a key regulatory event in LCAT activation [9], thus the amino acid exchange valine to methionine at codon 771 may affect functionality [10-12]. Login to comment 238 ABCA1 p.Val771Met Moreover, V771M is located very close to a putative transmembrane region (Fig. 4) and it is known that mutations in the SUR1 gene that are localized near the transmembrane region impair the interaction of this ABC transporter with Kir6.2 channel [13]. Login to comment 241 ABCA1 p.Arg1068Cys ABCA1 p.Trp840Arg ABCA1 p.Trp590Leu In the probands with HDL deficiency (patients B, C and D), we have identified three novel sequence variations: W840R, W590L and R1068C. Login to comment 242 ABCA1 p.Trp840Arg It is very likely, that amino acid exchange W840R in the 50-year-old female (patient B) is an additional Tangier mutation. Login to comment 244 ABCA1 p.Trp590Leu It can also be assumed that amino acid exchange W590L, found in patient C, is a mutation causing a defect ABCA1 protein product. Login to comment 245 ABCA1 p.Trp590Ser ABCA1 p.Trp590Leu This is supported by the fact that a mutation in the same codon was shown to cause Tangier disease (W590S) [7], but since the patient is only heterozygous for W590L, it remains unclear what additional mutation in ABCA1 causes the patients analphalipoproteinemia. Login to comment 246 ABCA1 p.Arg1068Cys It is very likely that the amino acid exchange R1068C, encountered in patient D, results in a defect or less active ABCA1 product. Login to comment 247 ABCA1 p.Arg1068Cys Although the mother, who is heterozygous for this sequence variation, was found to have quite normal HDL and apo A-I levels, the index patient who is compound heterozygous for R1068C and a known Tangier mutation ( (TC) in exon 23), showed analphalipoproteinemia. Login to comment 249 ABCA1 p.Arg1068Cys The father and the sister, who are heterozygous for the Tangier mutation and have no additional R1068C mutation, show typical reduced HDL levels but no analphalipoproteinemia. Login to comment 253 ABCA1 p.Val771Met Two mutations have been found in a phenotype related to CVD, located in an important domain of ABCA1 (carboxy-terminus) and a rare homozygous polymorphism (V771M) was identified in a proband with extremely high HDL. Login to comment