ABCMdb

ABCA1 p.Arg1068Cys

Predicted by SNAP2:	A: D (85%), C: D (91%), D: D (95%), E: D (91%), F: D (95%), G: D (91%), H: D (85%), I: D (91%), K: D (85%), L: D (91%), M: D (80%), N: D (91%), P: D (95%), Q: D (85%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Homology modeling and functional testing of an ABC... Atherosclerosis. 2011 Oct;218(2):404-10. Epub 2011 Jun 29. Suetani RJ, Sorrenson B, Tyndall JD, Williams MJ, McCormick SP
Homology modeling and functional testing of an ABCA1 mutation causing Tangier disease.
Atherosclerosis. 2011 Oct;218(2):404-10. Epub 2011 Jun 29., [PMID:21763656]

Abstract [show]
OBJECTIVE: To investigate the impact of the p.R1068H mutation on the structure and function of the ATP-binding cassette A1 (ABCA1) protein. METHODS: A homology model of the nucleotide binding domains of ABCA1 was constructed to identify the three-dimensional orientation of R1068. Cholesterol efflux assays were performed on fibroblasts obtained from members of a Tangier disease (TD) family carrying the p.R1068H mutation and in HEK293 cells transfected with a p.R1068H mutant cDNA vector. Confocal microscopy was used to investigate the localisation of the wildtype and mutant p.R1068H protein in HEK293 cells. RESULTS: Sequence alignments and modeling indicated residue R1068 to be located in an alpha-helix downstream of the Walker B motif in the first nucleotide binding domain (NBD-1), in a position to form ionic interactions with D1092 and E1093. Cholesterol efflux studies showed the efflux from TD fibroblasts and HEK293 cells expressing the mutant p.R1068H protein to be markedly reduced compared to wildtype. Localisation of the mutant p.R1068H protein in HEK293 cells showed intracellular retention of the protein indicating a defect in trafficking to the plasma membrane. CONCLUSION: Homology modeling of the ABCA1 protein showed that the p.R1068H mutation would likely disrupt the conformation of NBD-1. Functional studies of p.R1068H showed a lack of cholesterol efflux function due to defective trafficking to the plasma membrane, most likely caused by impaired oligomerisation.

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137 Indeed, SIFT predicts any residue substitution at position 1068 to be tolerated except R1068W which does not align with the observation that p.R1068H and the p.R1068C mutation are associated with extremely reduced HDL levels [11,23]. Login to comment

[hide] Promoter haplotype of a new ABCA1 mutant influence... Atherosclerosis. 2006 Aug;187(2):393-400. Epub 2005 Oct 12. 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., [PMID:16225879]

Abstract [show]
Mutations in the ATP-binding cassette A1 (ABCA1) transporter cause the high-density lipoprotein (HDL) deficiency syndromes of Tangier disease and familial hypoalphalipoproteinemia (FHA). Between individuals carrying ABCA1 mutations, the expression of FHA can be highly variable. Using denaturing HPLC (dHPLC) and direct promoter sequencing we screened the ABCA1 gene of a family with Tangier disease and variable expression of FHA. 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. Haplotyping of both 1068H alleles in the proband showed homozygosity in the coding region, however, the maternal 1068H allele had three single nucleotide polymorphisms (SNPs) in the promoter previously reported to be associated with reduced ABCA1 expression and HDL levels. An analysis of HDL levels based on 1068H allele haplotype showed the paternal 1068H heterozygotes to have the expected low HDL levels (0.67+/-0.16mmol/L), while maternal 1068H heterozygotes showed normal HDL levels (1.18+/-0.14mmol/L). Haplotype analysis of the wildtype allele amongst heterozygotes showed no haplotype that was common to the paternal or maternal side. We propose that the paternal 1068H ABCA1 allele causes a negative effect on the function of the wildtype allele and is associated with low HDL levels. In contrast, the maternal 1068H allele has less effect and is associated with a relatively normal HDL level. We conclude that haplotypes of mutant ABCA1 alleles may contribute to the phenotypic variance shown between FHA individuals.

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164 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

[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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10 In patients with HDL deficiency, three novel mutations have been identified (W590L, W840R and R1068C). Login to comment
59 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
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
196 which results in the amino acid exchange arginine to cysteine at codon 1068 (R1068C). Login to comment
200 The mother was found heterozygous for amino acid exchange R1068C (see pedigree D, Fig. 1). Login to comment
241 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
246 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 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 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

[hide] Novel mutations of ABCA1 transporter in patients w... Mol Genet Metab. 2012 Nov;107(3):534-41. doi: 10.1016/j.ymgme.2012.08.005. Epub 2012 Aug 18. Fasano T, Zanoni P, Rabacchi C, Pisciotta L, Favari E, Adorni MP, Deegan PB, Park A, Hlaing T, Feher MD, Jones B, Uzak AS, Kardas F, Dardis A, Sechi A, Bembi B, Minuz P, Bertolini S, Bernini F, Calandra S
Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency.
Mol Genet Metab. 2012 Nov;107(3):534-41. doi: 10.1016/j.ymgme.2012.08.005. Epub 2012 Aug 18., [PMID:22959828]

Abstract [show]
The objective of the study was the characterization of ABCA1 gene mutations in 10 patients with extremely low HDL-cholesterol. Five patients (aged 6 months to 76 years) presented with splenomegaly and thrombocytopenia suggesting the diagnosis of Tangier disease (TD). Three of them were homozygous for novel mutations either in intron (c.4465-34A>G) or in exons (c.4376delT and c.5449C>T), predicted to encode truncated proteins. One patient was compound heterozygous for a nucleotide insertion (c.1758_1759insG), resulting in a truncated protein and for a nucleotide substitution c.4799A>G, resulting in a missense mutation (p.H1600R). The last TD patient, found to be heterozygous for a known mutation (p.D1009Y), had a complete defect in ABCA1-mediated cholesterol efflux in fibroblasts, suggesting the presence of a second undetected mutant allele. Among the other patients, four were asymptomatic, but one, with multiple risk factors, had severe peripheral artery disease. Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. The pathogenic effect of the two intronic mutations (c. 1195-27G>A and c.4465-34A>G) was demonstrated by the analysis of the transcripts of splicing reporter mutant minigenes expressed in COS-1 cells. Both mutations activated an intronic acceptor splice site which resulted in a partial intron retention in mature mRNA with the production of truncated proteins. This study confirms the allelic heterogeneity of TD and suggests that the diagnosis of TD must be considered in patients with an unexplained splenomegaly, associated with thrombocytopenia and hypocholesterolemia.

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No. Sentence Comment
6 Three of these patients were heterozygous for known mutations (p.R130K+p.N1800H, p.R1068C, p.N1800H), while two were carriers of novel mutations (c.1195-27G>A and c.396_397insA), predicted to encode truncated proteins. Login to comment
176 PolyPhen (PSIC score) SIFT (P score) p.R130K Possibly damaging (1.540) Predicted tolerated p.R1068C Probably damaging (3.143) Predicted not tolerated (0.00) p.D1099Y Probably damaging (3.047) Predicted not tolerated (0.00) p.H1600R Probably damaging (3.197) Predicted not tolerated (0.02) p.N1800H Possibly damaging (1.845) Predicted tolerated termination codon (p.R587Afs*43) and ii) a single nucleotide substitution (c.4799A>G) in exon 36, resulting in a novel missense mutation (p.H1600R) (Table 1). Login to comment
222 3.9. Patient # Ge-9 3.9.1. Analysis of ABCA1 gene This patient was found to be heterozygous for a missense mutation (c.3202C>T, p.R1068C), previously described in a compound heterozygous patient [20]. Login to comment
223 In silico analysis predicted that the p.R1068C mutation was probably damaging (Table 2). Login to comment