ABCMdb

PMID: 10970771

Allikmets R
Simple and complex ABCR: genetic predisposition to retinal disease.
Am J Hum Genet. 2000 Oct;67(4):793-9. Epub 2000 Sep 1., [PubMed]

Sentences

No. Mutations Sentence Comment

29 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala What makes ABCR an even more difficult diagnostic target than CFTR is that, across all populations studied, the most-frequent disease-associated ABCR alleles-for example, G1961E, G863A/ delG863, and A1038V-have been described in ~10% of patients with STGD, whereas the delF508 allele of CFTR accounts for close to 70% of all cystic fibrosis alleles (Zielenski and Tsui 1995). Login to comment 40 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Second, both studies have identified a frequent, complex allele, L541P/A1038V, in patients of German origin who have both STGD and CRD (Maugeri et al. 2000 [in this issue]; Rivera et al. 2000 [in this issue]). Login to comment 43 ABCA4 p.Gly863Ala The earlier study by Maugeri et al. had defined the 2588GrC variant resulting in a dual effect, G863A/ delG863, as a founder mutation in northern-European patients with STGD (Maugeri et al. 1999). Login to comment 44 ABCA4 p.Thr1428Met Another ABCR allele, T1428M, which is very rare in populations of European descent, is apparently frequent (~8%) in the Japanese general population (Kuroiwa et al. 1999). Login to comment 46 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro In addition, the complexity of the genotype/phenotype-correlation studies in ABCR-related retinal dystrophies is underlined by the fact that two patients homozygous for the L541P/A1038V allele were diagnosed with CRD and STGD (Maugeri et al. 2000 [in this issue]; Rivera et al. 2000 [in this issue]). Login to comment 57 ABCA4 p.Asp2177Asn In 1997, a joint study by four laboratories suggested Table 1 Meta-analysis of Published Data on Two ABCR Alleles STUDY D2177N G1961Ea No. of Cases No of. Login to comment 69 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn In that study, the two most common AMD-associated variants, G1961E and D2177N, were genotyped in 1,218 unrelated patients with AMD and in 1,258 reportedly unaffected, matched controls. Login to comment 72 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn The risk of AMD was estimated to be increased approximately threefold in carriers of D2177N and approximately fivefold in carriers of G1961E. Login to comment 81 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn Note that the relative risk estimates calculated on the basis of the meta-analysis are also increased compared with those in the consortium study (Allikmets 2000) and are estimated at ~4 for the D2177N mutation and at ~7 for the G1961E variant. Login to comment 115 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn For example, they demonstrate that both ABCR variants analyzed in the consortium study, G1961E and D2177N, affect the protein function in vitro. Login to comment 116 ABCA4 p.Gly1961Glu The mutant G1961E protein, produced after the transfection of human embryonic kidney (293) cells with cloned cDNA, exhibits both several-fold-lower binding of 8-azido-ATP and dramatic inhibition of ATPase activity by retinal, compared with the wild-type ABCR protein. Login to comment 117 ABCA4 p.Asp2177Asn The D2177N variant had no effect on 8-azido-ATP binding but exhibited a reproducible elevation in ATPase activity, relative to the wild type (Sun et al. 2000). Login to comment 119 ABCA4 p.Gly1961Glu These results will also challenge several suggestions (Fishman et al. 1999; Lotery et al. 2000) that G1961E, the mutation most frequently found in patients with STGD and/or AMD, is indeed a benign variant in linkage disequilibrium with another disease-causing mutation. Login to comment 120 ABCA4 p.Gly863Ala Another issue that has been clarified is that of the functional significance of the G863A/delG863 variant. Login to comment 124 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Last, both mutations found on the "German" complex allele, L541P and A1038V, even if analyzed separately, render the ABCR protein defective (Sun et al. 2000). Login to comment