ABCMdb

ABCA4 p.Lys1148Thr

Predicted by SNAP2:	A: D (63%), C: D (66%), D: D (59%), E: D (59%), F: D (71%), G: D (59%), H: D (53%), I: D (63%), L: D (66%), M: D (66%), N: N (61%), P: D (66%), Q: N (57%), R: N (66%), S: N (57%), T: D (75%), V: D (63%), W: D (85%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, L: D, M: D, N: D, P: D, Q: D, R: N, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Late-onset Stargardt disease is associated with mi... Hum Genet. 2001 Apr;108(4):346-55. Yatsenko AN, Shroyer NF, Lewis RA, Lupski JR
Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4).
Hum Genet. 2001 Apr;108(4):346-55., [PMID:11379881]

Abstract [show]
Based on recent studies of the photoreceptor-specific ABC transporter gene ABCR (ABCA4) in Stargardt disease (STGD1) and other retinal dystrophies, we and others have developed a model in which the severity of retinal disease correlates inversely with residual ABCR activity. This model predicts that patients with late-onset STGDI may retain partial ABCR activity attributable to mild missense alleles. To test this hypothesis, we used late-onset STGDI patients (onset: > or =35 years) to provide an in vivo functional analysis of various combinations of mutant alleles. We sequenced directly the entire coding region of ABCR and detected mutations in 33/50 (66%) disease chromosomes, but surprisingly, 11/33 (33%) were truncating alleles. Importantly, all 22 missense mutations were located outside the known functional domains of ABCR (ATP-binding or transmembrane), whereas in our general cohort of STGDI subjects, alterations occurred with equal frequency across the entire protein. We suggest that these missense mutations in regions of unknown function are milder alleles and more susceptible to modifier effects. Thus, we have corroborated a prediction from the model of ABCR pathogenicity that (1) one mutant ABCR allele is always missense in late-onset STGD1 patients, and (2) the age-of-onset is correlated with the amount of ABCR activity of this allele. In addition, we report three new pseudodominant families that now comprise eight of 178 outbred STGD1 families and suggest a carrier frequency of STGD1-associated ABCR mutations of about 4.5% (approximately 1/22).

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Sentences [show]
No. Sentence Comment
90 In family AR632, individuals -04 and -05 have two ABCR alterations in exon 23 (R1129L and a novel mutation K1148T, 3443A→C) located between the first Walker B motif and a second transmembrane region of ABCR (Fig.2). Login to comment
93 N, C Amino or carboxy termini, asterisk novel missense ABCR mutation, bold numbers beginning and end of predicted functional motifs K1148T and the affected mother (onset at 49 years) carries the mutation R1129L. Login to comment
94 Affected siblings (onset at 11 and 32 years) are compound heterozygotes for mutations K1148T and R1129L. Login to comment