ABCMdb

ABCA4 p.Ile2113Met

ClinVar:	c.6339C>G , p.Ile2113Met ? , not provided
Predicted by SNAP2:	A: D (63%), C: N (57%), D: D (71%), E: D (59%), F: N (61%), G: D (75%), H: N (53%), K: D (59%), L: N (87%), M: N (53%), N: D (63%), P: D (66%), Q: D (75%), R: D (63%), S: N (53%), T: N (57%), V: N (87%), W: D (71%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Cosegregation and functional analysis of mutant AB... Hum Mol Genet. 2001 Nov 1;10(23):2671-8. Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.
Hum Mol Genet. 2001 Nov 1;10(23):2671-8., [PMID:11726554]

Abstract [show]
Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal recessively inherited retinopathies, including Stargardt disease (STGD), cone-rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.

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No. Sentence Comment
97 Pedigree Maternal allele Paternal allele AMD relative A priori Cosegregation AR19 pGM, -6 0.5 - AR33 [W1408R; R1640W] R24H and D1532N mA, -16 0.5 Yes AR59 4232insTATG C1488R pGM, -6 0.5 No AR80 T1526M pGF, -5 0.5 - AR80 T1526M mGF, -7 0.5 Yes AR125 4947delC C1488R pGM, -7 0.5 Yes AR215 [H1406Y; V2050L] pGM, -5 0.5 - AR218 2160+1G→C G1961E mA, -8 0.5 No AR262 W821R pGGF, -7 0.25 No AR271 P68R E1087K mGA, -6 0.25 No AR335 D645N F608I mGM, -9 0.5 Yes AR382 R1108C mGM, -6 0.5 Yes AR389 E2096K 5714+5G→A pGM, -8 0.5 Yes AR397 5196+1G→A 5585-1G→A mA, -5 0.5 No AR410 A1038V 768G→T pC, -5 0.25 Yes AR422 pGM, -6 0.5 - AR423 P1380L D1532N pGF, -4 0.5 No AR468 P1380L P1380L mU, -9 0.5 Yes AR484 L2027F G550R mGU, -5 0.25 Yes AR562 R2107H 3050+5G→A pGU, -5 0.25 No AR643 5196+2T→C L2027F mU, -4 0.5 Yes AR661 P1380L C54Y mGF, -6 0.5 Yes AR669 664del13 pGF, -4 0.5 No AR534 W821R P1380L pGM, -7 0.5 Yes (17) Family 1 R212C I2113M mGM, I-2 0.5 Yes (27) Family 2 R1108C R2107H mGM, I-2 0.5 Yes (27) Family 3 R212C G1977S mGF, I-1 0.5 Yes (27) 10.25 15 unlikely to account for many of the remaining alleles (our unpublished observations). Login to comment

[hide] Age-related macular degeneration in grandparents o... Am J Ophthalmol. 1999 Aug;128(2):173-8. Souied EH, Ducroq D, Gerber S, Ghazi I, Rozet JM, Perrault I, Munnich A, Dufier JL, Coscas G, Soubrane G, Kaplan J
Age-related macular degeneration in grandparents of patients with Stargardt disease: genetic study.
Am J Ophthalmol. 1999 Aug;128(2):173-8., [PMID:10458172]

Abstract [show]
PURPOSE: To report clinical features and molecular genetic study in three unrelated families in which age-related macular degeneration was observed in grandparents of patients with Stargardt disease. METHODS: A complete ophthalmologic examination including best-corrected visual acuity measurement, fundus examination, and fluorescein angiography was performed on all members of the three families. The entire coding sequence of the ABCR gene was analyzed using a combination of single strand conformation polymorphism and direct sequence analysis of the 50 exons. RESULTS: Compound heterozygous missense mutations were observed in patients with Stargardt disease (Arg212Cys, Argl107Cys, Gly1977Ser, Arg2107His, and le2113Met). Heterozygous missense mutations were observed in the grandparents with age-related macular degeneration (Arg212Cys and Arg1107Cys). CONCLUSIONS: We report phenotype and genotype findings in three unrelated families segregating patients with Stargardt disease and age-related macular degeneration. The hypothesis that the Arg212Cys and Arg1107Cys ABCR gene mutations could be susceptibility factors for age-related macular degeneration is discussed. We speculate that the relatives of patients affected with Stargardt disease who are carriers of heterozygous ABCR gene mutations may have a higher risk of developing age-related macular degeneration.

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46 Compound heterozygous missense mutations were observed in patients with Stargardt disease: Arg212Cys and Ile2113Met (III.1 and III.2, family 1), Arg1107Cys and Arg2107His (III.1 and III.2, family 2), Arg212Cys and Gly1977Ser (III.1 family 3) (Figure 1). Login to comment
56 Clinical Data of Individuals From the Three Pedigrees Individual, Family Age (yrs) Visual Acuity Macular Involvement (fundus examination and FA) Genotype*RE LE I.2, fam 1 78 CF CF RPE atrophy, some hard drusen and choroidal new vessel (Figure 2, top left) Arg212Cys/wt I.2, fam 2 86 CF CF Progressive geographic atrophy since the age of 80 (Figure 2, top right) Arg1107Cys/wt I.1, fam 2 75 20/30 20/40 Patches of RPE atrophy and perimacular soft drusen (Figure 2, middle left) Arg212Cys/wt I.2, fam 3 72 20/20 20/20 None wt/wt II.1, fam 1 44 20/20 20/20 None Ile2113Met/wt II.2, fam 1 50 20/20 20/25 Diffuse hard drusen (Figure 2, middle right) Arg212Cys/wt II.1, fam 2 70 20/20 20/20 None Arg2107His/wt II.2, fam 2 66 20/20 20/25 Diffuse hard drusen (Figure 2, bottom) Arg1107Cys/wt II.1, fam 3 37 20/20 20/20 None Gly1977Ser/wt II.2, fam 3 39 20/20 20/20 None Arg212Cys/wt III.1, fam 1 10 20/200 20/200 RPE atrophy, fundus flavimaculatus and choroidal silent Arg212Cys/Ile2113Met III.2, fam 1 6 20/20 20/20 None Ile2113Met/wt III.1, fam 2 33 20/200 CF RPE atrophy, fundus flavimaculatus and choroidal silent Arg1107Cys/Arg2107His III.2, fam 2 28 CF CF RPE atrophy, fundus flavimaculatus and choroidal silent Arg1107Cys/Arg2107His III.3, fam 2 24 20/20 20/20 None Arg2107His/wt III.1, fam 3 12 CF 20/200 RPE atrophy, fundus flavimaculatus and choroidal silent Arg212Cys/Gly1977Ser III.2, fam 3 9 20/20 20/20 None wt/wt CF ϭ counting fingers; FA ϭ fluorescein angiography; None ϭ no macular degeneration; RPE ϭ retinal pigment epithelium; wt ϭ wild type. Login to comment