ABCMdb

PMID: 11384574

Shroyer NF, Lewis RA, Lupski JR
Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease?
Am J Ophthalmol. 2001 Jun;131(6):761-6., [PubMed]

Sentences

No. Mutations Sentence Comment

50 ABCA4 p.Arg1129Cys Subject 3 is heterozygous for the transition 3385C3T, which encodes the missense substitution Arg1129Cys. Login to comment 51 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Cys This alteration was reported previously in an unrelated patient with Stargardt disease.23 In addition, the missense substitution of leucine for arginine at this residue (Arg1129Leu) was reported in an unrelated patient with age-related macular degeneration and two unrelated patients with Stargardt disease.18,23 Thus, the mutation Arg1129Cys is considered pathogenic and may predispose the development of retinopathy in the heterozygous state. Subject 7 carries three missense mutations. Login to comment 52 ABCA4 p.Leu1201Arg He is heterozygous for the transversion 3602T3G, which encodes the missense substitution Leu1201Arg. Login to comment 53 ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Leu1201Arg This alteration was reported previously in an unrelated patient with Stargardt disease.23 In addition, subject 7 is homozygous for the transition 6320G3A, which encodes the missense substitution Arg2107His, reported previously in six unrelated patients with Stargardt disease.24-26 Thus, subject 7 is compound heterozygous for both the missense mutation Arg2107His and for the complex allele (Leu1201Arg; Arg2107His). Login to comment 54 ABCA4 p.Arg212His ABCA4 p.Ser2255Ile Subject 7 is also heterozygous for two missense polymorphisms: the transition 635G3A which encodes the substitution Arg212His, and the transversion 6764G3T which encodes the substitution Ser2255Ile. Login to comment 60 ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Asn1868Ile ABCA4 p.His423Arg ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCR Coding Alterations in Patients With Chloroquine and Hydroxychloroquine Retinopathy Exon Nucleotide* Amino Acid* Patient Number 1 2 3 4 5 6 7 8 6 635 Arg212His G/G G/G G/G G/G G/G G/G A/G G/G 10 1268 His423Arg A/A A/A A/A G/G A/A A/A A/A A/A 1269 His423His C/C C/C C/C C/C C/C C/T C/T C/C 20 2964 Leu988Leu C/C C/C C/C C/C C/C C/C C/T C/C 23 3385 Arg1129Cys† C/C C/C C/T† C/C C/C C/C C/C C/C 24 3602 Leu1201Arg† T/T T/T T/T T/T T/T T/T T/G† T/T 28 4203 Pro1401Pro C/C C/C C/C C/A C/A C/C C/C C/C 40 5603 Asn1868Ile A/A A/A A/A A/T A/T A/A A/A A/A 5682 Leu1894Leu G/G G/C G/C G/C G/C G/G C/C G/G 41 5814 Leu1938Leu A/A A/G A/G A/A A/A A/A G/G A/A 42 5844 Pro1948Pro A/A A/G A/G A/A A/A A/A G/G A/A 44 6069 Ile2023Ile C/C C/C C/C C/C C/C C/T C/C C/T 45 6249 Ile2083Ile C/C C/C C/C C/C C/C C/T C/C C/T 46 6285 Asp2095Asp T/T T/T T/T T/T T/T T/T C/C T/C 6320 Arg2107His† G/G G/G G/G G/G G/G G/G A/A† G/G 49 6764 Ser2255Ile G/G G/G G/G G/G G/G G/G G/T G/T *Standard amino acid and nucleotide abbreviations are used. Login to comment 62 ABCA4 p.His423Arg mozygous for the transition 1268A3G, which encodes the missense substitution His423Arg. Login to comment 63 ABCA4 p.Asn1868Ile Subject 4 is also heterozygous for the transversion 5603A3T, which by conceptual translation results in the substitution of Ile for Asn (Asn1868Ile). Login to comment 64 ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile Subject 5 is heterozygous for the substitution Asn1868Ile, and subject 8 is heterozygous for the substitution Ser2255Ile. Login to comment 71 ABCA4 p.Arg1129Cys Subject 3 is heterozygous for the mutation Arg1129Cys. Login to comment 73 ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Leu1201Arg ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Cys Also, recent biochemical characterization of recombinant ABCR protein with the Arg1129Leu mutation revealed a substantial reduction in both expression and ATP binding when compared with wild type ABCR.27 Thus, the pathogenic allele Arg1129Cys is likely to cause severe reduction in ABCR activity and may predispose development of chloroquine/hydroxychloroquine maculopathy in the heterozygous state. Subject 7 is compound heterozygous for the missense mutation Arg2107His and the complex allele (Leu1201Arg; Arg2107His). Login to comment 74 ABCA4 p.Arg212His ABCA4 p.Ser2255Ile In addition, he is a carrier of two missense polymorphisms, Arg212His and Ser2255Ile. Login to comment 75 ABCA4 p.Arg212His ABCA4 p.Ser2255Ile The Arg212His alteration was found in eight of 182 control chromosomes (4.4%), whereas the Ser2255Ile alteration was reported in six of 116 control chromosomes (5.2%). Login to comment 76 ABCA4 p.Arg2107His ABCA4 p.Leu1201Arg Neither the Leu1201Arg nor the Arg2107His mutations was identified in 160 control chromosomes. Login to comment 77 ABCA4 p.Arg2107His The Arg2107His mutation has also been biochemically characterized by Sun and associates,27 who report a moderate effect on expression level and reduced ATP binding of this mutant protein. Login to comment 78 ABCA4 p.Arg2107His ABCA4 p.Leu1201Arg It is unknown how the combinations of the Leu1201Arg and Arg2107His mutations may combine to reduce ABCR activity; however, we predict that subject 7 may have very low remaining ABCR activity. Login to comment