ABCMdb

PMID: 16343503

Alrasadi K, Ruel IL, Marcil M, Genest J
Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency.
Atherosclerosis. 2006 Oct;188(2):281-91. Epub 2005 Dec 15., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCA1 p.Gly616Val ABCA1 p.Asn1800His ABCA1 p.Gln2210His ABCA1 p.Phe1840Leu ABCA1 p.Leu1869* However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Login to comment 6 ABCA1 p.Arg1851* ABCA1 p.Ser1731Cys ABCA1 p.Lys776Asn Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Login to comment 74 ABCA1 p.Arg909* We have previously reported the identification of mutations at the ABCA1 gene in four of these probands (R2084X; del ED1893,4; del L693 and R909X), a finding that led to the identification of the ABCA1 gene in Tangier disease and familial HDL deficiency [8,9]. Login to comment 86 ABCA1 p.Gly616Val ABCA1 p.Asn1800His ABCA1 p.Arg909* ABCA1 p.Gln2210His ABCA1 p.Arg1851* ABCA1 p.Ser1731Cys ABCA1 p.Ser1731Cys ABCA1 p.Ser1731Cys ABCA1 p.Phe1840Leu ABCA1 p.Leu1869* ABCA1 p.Gly2160Thr Table 2 Mutations of the ABCA1 gene in French-Canadian probands with HDL deficiency and defective cellular lipid efflux Probandsa Gene region Nucleotide change Amino acid change Predicted effect by Polyphenb Reference ABE Exon 48 C6370T R2084X Truncated protein [8,9] MGA Exon 14 del 2017-2019 del L693 Probably damaging [8,9] ALA Exon 41 del 5618-5623 del ED1893,4 Probably damaging [8,9] RLA Exon 18 C2665T R909X Truncated protein [8,9] RDU Exon 41 C5864T R1851X Truncated protein [4] SBO Exon 40 A5711C N1800H Possibly damaging [27] Exon 49 G6943C Q2210H Probably damaging - RPH Exon 14 G2160T G616V Probably damaging - GOB Exon 41 del 5833 fs F1840L, L1869X Truncated protein - LNO Exon 38 C5505G S1731C Possibly damaging [4] VDU Exon 38 C5505G S1731C Possibly damaging [4] RRI Exon 38 C5505G S1731C Possibly damaging [4] PCH Exon 16 G2641C K776N Possibly damaging [5] GCH - - - - - LBO - - - - - a Probands refer to subjects ID # 301 in the pedigrees. b Polyphen computer software (http://www.bork.embl-heidelberg.de/polphen/). Login to comment 109 ABCA1 p.Arg909* In the original four probands (ABE, R2084X; MGA, del L693; ALA, del ED1893,4; RLA, R909X), the mutations in the ABCA1 gene were associated with a functional impairment of the mature protein [8,9]. Login to comment 110 ABCA1 p.Arg1851* In the remaining eight probands, we identified a previously reported mutation [4], R1851X, in proband RDU that perfectly segregated with the low HDL-C trait in the kindred (Fig. 2A). Login to comment 111 ABCA1 p.Asn1800His ABCA1 p.Gln2210His In another proband, SBO, we identified heteroallelic mutations N1800H (previously reported in Tangier disease [27]) and a novel mutation, Q2210H, which is predicted to be probably damaging to the protein by the computer program Polyphen. Login to comment 113 ABCA1 p.Gly616Val In proband RPH (Fig. 2C), a novel mutation was identified, G616V, and is predicted to be probably damaging. Login to comment 116 ABCA1 p.Leu1869* A novel frameshift mutation, leading to a pre- dictedtruncationoftheprotein,wasdetectedinprobandGOB (fsF1840L, L1869X; Table 2). Login to comment 117 ABCA1 p.Ser1731Cys The patient`s family declined participationinthestudy.Inthreeotherprobands,LNO,VDU and RRI, Table 1, the previously reported S1731C mutation [4] was found. Login to comment 123 ABCA1 p.Ser1731Cys (Continued ) S1731C mutation while phospholipid efflux was relatively preserved. Login to comment 124 ABCA1 p.Lys776Asn Lastly, in proband PCH, we found the previously reported K776N, which did not show an unequivocal segregation within the family members (Fig. 2G). Login to comment 129 ABCA1 p.Gln2210His These variants, which are highlighted, were not observed in 528 chromosomes examined from subjects with normal HDL-C levels, except the Q2210H, which was present in <1% (data not shown). Login to comment 136 ABCA1 p.Phe1840Leu ABCA1 p.Leu1869* A novel frameshift mutation, F1840L, L1869X, was reported in proband GOB. Login to comment 140 ABCA1 p.Asn1800His ABCA1 p.Gln2210His Single amino acid substitutions were identified in the six remaining subjects, with one proband heteroallelic for the N1800H and Q2210H mutation (a novel mutation, predicted to be probably damaging to the protein). Login to comment 142 ABCA1 p.Asn1800His In fact, the N1800H mutation in the ABCA1 gene has been previously reported in a case of Tangier disease [27] in a patient homozygous for this mutation. Login to comment 143 ABCA1 p.Gly616Val We, also, identified a novel variant, the G616V mutation in the ABCA1 gene, in proband RPH. Login to comment 146 ABCA1 p.Lys776Asn Proband PCH (Fig. 2G) was bearing the previously reported K776N mutation [5], predicted to be possibly damaging. Login to comment 149 ABCA1 p.Ser1731Cys Three probands, LNO, VDU and RRI were carriers of the previously reported S1731C mutation, an ABCA1 gene defect that has been found in French Canadians only [4]. Login to comment 151 ABCA1 p.Ser1731Cys While the cellular cholesterol efflux was markedly reduced in the three cell lines with the S1731C mutation (63, 66 and 68% of controls), phospholipid efflux was only modestly reduced (84, 74 and 83% of controls). Login to comment 178 ABCA1 p.Ser1731Cys As our patients are of French-Canadian descent, the possibility of a founder effect is also highlighted by the finding that 3/12 probands were sharing the same ABCA1 mutation (S1731C), a typical French-Canadian mutation [4]. Login to comment