ABCMdb

PMID: 16225879

Slatter TL, Williams MJ, Frikke-Schmidt R, Tybjaerg-Hansen A, Morison IM, McCormick SP
Promoter haplotype of a new ABCA1 mutant influences expression of familial hypoalphalipoproteinemia.
Atherosclerosis. 2006 Aug;187(2):393-400. Epub 2005 Oct 12., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCA1 p.Arg1068His A new mutation (R1068H) within the first ATP-binding domain was identified in homozygous form in the Tangier disease individual and was present in several family members. Login to comment 35 ABCA1 p.Arg1068His (A) Pedigree and genotype of the R1068H family. Login to comment 36 ABCA1 p.Arg1068His The proband with Tangier disease (represented by an arrow and filled circle) is homozygous for the R1068H mutation. Login to comment 40 ABCA1 p.Arg1068His (B) Detection of the R1068H mutation by dHPLC. Login to comment 41 ABCA1 p.Arg1068His The dHPLC profiles of the exon 22 amplicon of three members of the R1068H family are shown. Login to comment 44 ABCA1 p.Arg1068His (C) Detection of the R1068H mutation by DNA sequencing. Login to comment 47 ABCA1 p.Arg1068His The mutation predicts an arginine to histidine substitution at amino acid 1068 in the ABCA1 protein. Login to comment 83 ABCA1 p.Arg1068His Statistical analysis The Mann-Whitney test was used to compare the mean differences in lipid levels in the presence and absence of the R1068H mutation and in the presence of the maternal versus paternal 1068H allele in heterozygotes. Login to comment 89 ABCA1 p.Arg1068His ABCA1 p.Arg1068His An HDL-C measurement was not available Table 1 Plasma lipid levels and genotypes in the R1068H family Subject Sex Age TC TG LDL-C HDL-C R1068H II:2 M 76 5.40 1.20 3.50 1.37 -/- II:3 M 66 5.70 1.60 3.30 1.63 -/- II:4 F 67 6.07 2.62 3.75 1.12 +/- II:5a M 58 3.90 0.63 NT II:7 F 60 7.10 2.10 4.60 1.53 -/- II:8 M 66 5.10 2.60 3.30 0.60 +/- III:1 F 46 5.40 1.00 3.60 1.39 -/- III:3 F 42 3.50 1.50 2.80 0.04 +/+ III:4 M 38 4.00 0.60 2.50 1.22 +/- III:5 F 49 5.40 0.90 2.70 2.26 -/- III:6 M 48 6.50 2.02 4.60 1.00 -/- III:7 F 44 3.98 1.31 2.90 0.48 +/- III:8 F 40 7.50 1.42 5.85 1.08 -/- III:9 F 41 2.60 0.70 1.70 0.60 +/- III:10 F 37 4.50 1.10 3.10 0.90 +/- III:11 M 35 5.53 1.20 4.02 1.10 -/- IV:1 F 23 3.60 0.40 2.40 1.03 +/- IV:2 F 21 4.00 0.80 2.30 1.35 +/- IV:3 F 24 3.50 0.50 2.50 0.76 +/- TC indicates total cholesterol; TG, triglycerides; HDL-C, high-density cholesterol; LDL-C low-density cholesterol. All measurements are expressed in mmol/L. Login to comment 90 ABCA1 p.Arg1068His ABCA1 p.Arg1068His (-/-) wildtype; (+/-) heterozygous for the R1068H mutation; (+/+) homozygote for the R1068H mutation. Login to comment 104 ABCA1 p.Arg1068His (A) Schematic diagram showing the position of the R1068H mutation within the ATP-binding region of ABCA1. Login to comment 106 ABCA1 p.Arg1068His (B) Alignment of the ABCA protein sequences from different species around the R1068H region. Login to comment 111 ABCA1 p.Arg1068His A computer analysis of the effect of the R1068H mutation on ABCA1 function using PolyPhen (www.bork.embl-heidelberg.de/PolyPhen) predicts that the mutation is "possibly damaging". Login to comment 114 ABCA1 p.Arg1068His Sequencing of exon 22 from the nine family members containing the exon 22 heteroduplex revealed them all to be heterozygous for the R1068H mutation (Fig. 1A). Login to comment 115 ABCA1 p.Arg1068His The R1068H mutation was absent in all other family members. Login to comment 136 ABCA1 p.Arg1068His ABCA1 p.Arg1068His Table 2 Mean plasma lipid and lipoprotein levels in the R1068H family based on genotype R1068H Genotype Sex Age TC TG LDL-C HDL-C M F -/- (n = 8) 4 4 53 ± 14 6.07 ± 0.85 1.43 ± 0.45 4.02 ± 0.98 1.42 ± 0.40 -/+ (n = 9) 7 2 40 ± 17 4.15 ± 0.99* 1.18 ± 0.86 2.72 ± 0.61** 0.90 ± 0.31*** -/+m (n = 4) 1 4 37 ± 21 4.42 ± 1.12 1.10 ± 1.02 2.74 ± 0.68 1.18 ± 0.14 -/+p (n = 5) 1 3 42 ± 15 3.94 ± 0.96**** 1.24 ± 0.82 2.70 ± 0.63***** 0.67 ± 0.16******,******* TC indicates total cholesterol; TG, triglycerides; HDL-C, high-density cholesterol; LDL-C low-density cholesterol. All measurements are expressed in mmol/L. Login to comment 137 ABCA1 p.Arg1068His ABCA1 p.Arg1068His ABCA1 p.Arg1068His (-/-), wildtype; (+/-), heterozygous for the R1068H mutation; (-/+m), heterozygous for the maternal R1068H allele; (-/+p), heterozygous for the paternal R1068H allele. Login to comment 151 ABCA1 p.Arg1068His A further analysis of lipid levels based on genotype (Table 2) revealed a significantly lower mean total cholesterol, LDL-C and HDL-C in R1068H heterozygotes compared to unaffected family members (4.15 ± 0.99 mmol/L versus 6.07 ± 0.85 mmol/L, p = 0.003; 2.72 ± 0.61 mmol/L versus 4.02 ± 0.98 mmol/L, p = 0.006 and 0.90 ± 0.31 mmol/L versus 1.42 ± 0.40 mmol/L, p = 0.012, respectively). Login to comment 159 ABCA1 p.Arg1068His In the current study, we report a new mutation (R1068H) within the first ATP-binding cassette of ABCA1. Login to comment 164 ABCA1 p.Arg1068Cys Furthermore, a different mutation of the same amino acid (R1068C) has recently been reported in a compound heterozygote with virtually no HDL [15]. Login to comment 165 ABCA1 p.Arg1068His Since the R1068H mutation is likely to produce a dysfunctional protein, one would expect it to be associated with FHA in the heterozygous state. Login to comment 187 ABCA1 p.Arg1068His ABCA1 p.Arg1068His Furthermore, a recent sequence analysis of the 3 untranslated region of both R1068H alleles has revealed a SNP(NCBISNPIDNumberrs4149341)inthepaternalallele (T Slatter, unpublished data), which strengthens the case for non-consanguinity. Login to comment