ABCMdb

PMID: 20800056

Berge KE, Leren TP
Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol.
Clin Chim Acta. 2010 Dec 14;411(23-24):2019-23. Epub 2010 Aug 25., [PubMed]

Sentences

No. Mutations Sentence Comment

59 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Asn1800His ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Leu1244Gln ABCA1 p.Arg1680Gln ABCA1 p.Cys1429* ABCA1 p.Glu1172Asp ABCA1 p.Val1674Ile ABCA1 p.Arg282Gln ABCA1 p.Val399Ala ABCA1 p.Cys1477Phe ABCA1 p.Cys887Phe ABCA1 p.Met636Val of patients (het/hom)a Mutation Nucleotide Exon/Intron (i) PolyPhen prediction (score) SNP rs ID, ref.# ABCA1 Missense 8/3 R219K c.656, GNA 7 Benign (0.489) rs2230806 0/1 R282Q c.845, GNA 9 Benign (0.592) Novel 1/0 V399A c.1196, TNC 11 Benign (0.040) rs9282543 1/0 M636V c.1906, ANG 15 Benign (0.418) Novel 3/0 V771M c.2311, GNA 16 Benign (0.931) rs2066718 2/0 V825I c.2473, GNA 17 Benign (0.440) rs2066715 3/1 I883M c.2649, ANG 18 Benign (0.147) rs2066714 1/0 C887F c.2660, GNT 19 Benign (0.888) Novel 3/0 E1172D c.3516, GNC 24 Benign (0.546) rs33918808 1/0 G1216V c.3647, GNT 25 Prob damb (2.154) Ref. [18] 1/0 L1244Q c.3731, TNA 25 Prob dam (2.269) Novel 1/0 C1477F c.4430, TNA 31 Prob dam (3.688) Ref. [17] 14/1 R1587K c.4760, ANT 35 Benign (0.284) rs2230808 1/0 V1674I c.5020, GNA 37 Benign (0.821) Novel 1/0 R1680Q c.5039, GNA 37 Poss damc (1.926) Ref. [17] 1/0 N1800H c.5398, ANC 40 Poss dam (1.845) Ref. [19] Nonsense/splice 1/0 IVS4+1, GNA c.302+1, GNA i4 - 1/0 C1429X c.4287, CNA 31 - 1/0 IVS32+1, GNA c.4559+1, GNA i32 - APOA-I 7/0 R160L c.551, GNT 4 Prob dam (2.491) Ref. [21] 1/0 del182K del c.616-618 AAG 4 - Novel a Het: heterozygote, hom: homozygote. Login to comment 65 ABCA1 p.Cys1429* Nonsense mutations and splice-site mutations in the ABCA1 gene One patient was heterozygous for nonsense mutation C1429X in exon 9 of the ABCA1 gene, and two patients were heterozygous for the novel splice-site mutations IVS4+1, GNA (c.302+1, GNA) in intron 4 and IVS32+1, GNA (c.4559+1, GNA) in intron 32, respectively. Login to comment 66 ABCA1 p.Cys1429* Since mutation C1429X causes a premature stop codon and IVS4+1, GNA, and IVS32+1, GNA affect nucleotide +1 of the respective consensus splice sites, these three mutations should all be considered pathogenic. Login to comment 68 ABCA1 p.Leu1244Gln ABCA1 p.Val1674Ile ABCA1 p.Arg282Gln ABCA1 p.Cys887Phe ABCA1 p.Met636Val Missense mutations in the ABCA1 gene To our knowledge, mutations R282Q, M636V, C887F, L1244Q, and V1674I are novel mutations. Login to comment 70 ABCA1 p.Leu1244Gln Considering PolyPhen prediction scores, mutation L1244Q was predicted to be probably damaging, while the others were predicted to be benign. Login to comment 71 ABCA1 p.Val1674Ile ABCA1 p.Arg282Gln ABCA1 p.Cys887Phe One patient was homozygous for mutation R282Q, and one was compound heterozygous for mutations C887F and V1674I. Login to comment 74 ABCA1 p.Asn1800His ABCA1 p.Cys1477Phe ABCA1 p.Gly1216Val Three patients were heterozygous for ABCA1 mutations G1216V, C1477F, and N1800H that have been reported to be associated with low HDL cholesterol levels [17-19]. Login to comment 75 ABCA1 p.Arg1680Gln One patient was heterozygous for mutation R1680Q, which has previously been found in a patient with a high level of HDL cholesterol [17]. Login to comment 76 ABCA1 p.Arg1680Gln Thus, at face value, it is likely that this mutation is a normal genetic variant, although none of the 100 control individuals were heterozygous for mutation R1680Q. Login to comment 77 ABCA1 p.Arg1680Trp However, an arginine at position 1680 appears to be important for the normal function of ABCA1, as demonstrated by the observation that a Japanese Tangier disease patient was homozygous for mutation R1680W [20]. Login to comment 78 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Val399Ala Variants R219K, V399A, V771M, V825I, I883M, E1172D, and R1587K have been reported as single nucleotide polymorphisms (SNPs) (Table 1). Login to comment 79 ABCA1 p.Val399Ala Except for V399A, these nonsynonymous SNPs were observed in two or more patients included in this study. Login to comment 80 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp In addition, R219K, V771M, V825I, I883M, E1172D, and R1587K have been found in similar frequencies in patients with low or high HDL cholesterol levels [18], indicating that these variants do not cause low HDL cholesterol levels. Login to comment 88 ABCA1 p.Asn1800His ABCA1 p.Leu1244Gln ABCA1 p.Cys1429* ABCA1 p.Val1674Ile ABCA1 p.Arg282Gln ABCA1 p.Cys1477Phe ABCA1 p.Cys887Phe ABCA1 p.Met636Val ABCA1 p.Gly1216Val HDL cholesterol levels in individuals carrying a pathogenic mutation in the ABCA1 or apoA-I genes Both the two identified apoA-I mutations and the following ABCA1 mutations were considered pathogenic: the nonsense mutation (C1429X); the two splice-site mutations (IVS4 +1, G NA and IVS32+1, GNA ); novel mutations R282Q, M636V, C887F, L1244Q, and V1674I; and mutations previously reported to be associated with low HDL cholesterol levels (G1216V, C1477F and N1800H). Login to comment 116 ABCA1 p.Asn1800His ABCA1 p.Cys1477Phe ABCA1 p.Gly1216Val This has been shown for mutations G1216V, C1477F, and N1800H [11,17], thereby explaining the mechanism for the low HDL cholesterol levels in carriers of these mutations. Login to comment 119 ABCA1 p.Leu1026Pro ABCA1 p.Glu1386Gln Two mutations identified in their study, L1026P and E1386Q, were predicted to be benign based on the PolyPhen scores but were shown by in vitro cholesterol efflux assays to reduce cholesterol efflux. Login to comment 122 ABCA1 p.Val399Ala Mutation V399A, for example, was predicted by PolyPhen as benign but was found by Vaughan et al. [24] to reduce cholesterol efflux. Login to comment 124 ABCA1 p.Val399Ala Based on this controversy, we decided to consider V399A in ABCA1 as a normal variant. Login to comment 126 ABCA1 p.Val1674Ile ABCA1 p.Arg282Gln ABCA1 p.Cys887Phe Although the HDL cholesterol levels in the two patients who were homozygous for R282Q and compound heterozygous for C887F and V1674I, respectively, were higher than usually found in Tangier disease, these mutations may still represent mild mutations, which make the mutant protein retain some functional activity. Login to comment