ABCMdb

PMID: 24632595

Zhou Y, Tao S, Chen H, Huang L, Zhu X, Li Y, Wang Z, Lin H, Hao F, Yang Z, Wang L, Zhu X
Exome sequencing analysis identifies compound heterozygous mutation in ABCA4 in a Chinese family with Stargardt disease.
PLoS One. 2014 Mar 14;9(3):e91962. doi: 10.1371/journal.pone.0091962. eCollection 2014., [PubMed]

Sentences

No. Mutations Sentence Comment

8 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* Compound heterozygous variants p.Y808X and p.G607R of the ATP-binding cassette, sub-family A (ABC1), member 4 (ABCA4) gene, which encodes the ABCA4 protein, a member of the ATP-binding cassette (ABC) transport superfamily, were identified as causative mutations for Stargardt disease of this family. Login to comment 39 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* Our results identified two compound heterozygous disease-segregating mutations, c.C2424G, p.Y808X and c.G1819A, p.G607R, in the ABCA4 gene. Login to comment 67 ABCA4 p.Gly607Arg ABCA4 p.Gly607Arg ABCA4 p.Gly607Arg ABCA4 p.Gly607Arg Family Member Age Gender Disease Duration (years) Visual Acuity (OD, OS) Mutation(s) Original reports described Nucleotide change Effect I1 43 M 0 20/20, 20/20 1819G.A Gly 607 Arg Andrea Rivera I2 43 F 0 20/20, 20/20 2424C.G Tyr 808* N/A II1 13 M 3 20/400, 20/400 1819G.A/2424C.G Gly 607 Arg,/Tyr 808* Andrea Rivera,N/A II2 18 F 8 20/400, 20/400 1819G.A/2424C.G Gly 607 Arg,/Tyr 808* Andrea Rivera,N/A II3 20 F 0 20/20, 20/20 1819G.A Gly 607 Arg Andrea Rivera N/A, Not available; M, Male; F, Female. Login to comment 109 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* In both patients we found two mutations c.C2424G (p.Y808X) and c.G1819A (p.G607R) satisfying a recessive compound heterozygous inheritance model (Table 3) in the gene ABCA4 (NM_000350.2). Login to comment 110 ABCA4 p.Gly607Arg When we checked the human gene mutation database (http://www.hgmd.org/), we found that mutation p.G607R was reported by Andrea Rivera in 2000 [24]. Login to comment 111 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* Sanger sequencing confirmed these two mutations in the two affected siblings and demonstrated that their parents were unaffected carriers of Y808X (father) and G607R (mother) mutations, showing complete co-segregation of the mutations with the disease phenotype (Figure 3). Login to comment 113 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* These data, together with the clinical presentation of the two affected siblings, demonstrated that p.G607R and p.Y808X variants in the gene ABCA4 was responsible for Stargardt disease in this family. Login to comment 115 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* The previously reported mutation p.G607R of ABCA4 was predicted to be damaging and the novel mutation c.C2424G, p.Y808X in the affected families introduced a stop codon, which removed 1465 amino acids from the ABCA4 protein (2273 amino acids), according to GenBank accession number NM_000350.2. Login to comment 118 ABCA4 p.Gly607Arg ABCA4 p.Gly607Arg Mutation p.G607R, located within exon 13, results in changes of a hydrophilic glycine to an arginine at position 607, which may lead to a damaging replacement with a score of 0.99 (sensitivity:0.72, specificity:0.97) Figure 4A. Login to comment 119 ABCA4 p.Tyr808* Mutation Y808X, located within exon 16, results in a nonsense mutation, and the mRNA with a premature stop codon is likely to be degenerated by the nonsense-mediated mRNA decay response, thus leading to a decrease in ABCA4 expression. Login to comment 131 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* Our result also indicated that G607R occurs in the ECD1 domain, while Y808X occurs in the disc lumen region between TMD1 (Figure 4B). Login to comment 146 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* (A) Protein alignment showed conservation of residues ABCA4 Y808X and G607R across nine species. Login to comment 148 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* The ABCA4 mutation G607R occured in the NBD1 while Y808X occured in the disc lumen region between TMD1. Login to comment 157 ABCA4 p.Gly607Arg ABCA4 p.Tyr808* In our study compound heterozygous mutations p.Y808X and p.G607R of the ABCA4 gene were identified. Login to comment 158 ABCA4 p.Gly607Arg The previously reported ABCA4 p.G607R mutation [24,50] in exon 13 is a single nucleotide polymorphism, rs61749412, which is predicted probably to be damaging to protein function (PolyPhen2 scores close to 1.0). Login to comment 159 ABCA4 p.Gly607Arg Through the analysis of membrane topology by TMHMM2.0, we found that the p.G607R mutation was in the ABCA4 ECD1 region, which is involved in stacking interactions with the adenine ring of ATP [51]. Login to comment 160 ABCA4 p.Gly818Glu ABCA4 p.Tyr808* The novel stopgain p.Y808X mutation in exon 16 was detected in a heterozygous state, close to the previously reported mutation p.G818E [11]. Login to comment