Molecular Genetics of an Autosomal Dominant Late-Onset Macular Degeneration With Nonexudative and Exudative Macular Pathology: Evidence for a Possible Selective Bias for Gametes Carrying the Disease Causing Mutation

Abstract

Abstract: : Purpose. We have recently identified a large family (SUNY901) whose members manifest a wide range of atrophic and exudative macular degenerative disease. The study below will explore the molecular genetic basis and phenotypic characteristics of this unusual late-onset autosomal dominant macular degeneration with features of age-related macular degeneration. Methods. A total of 17 affected members, 17 clinically unaffected members, and 5 spouses from SUNY901 were recruited for the study. Clinical analysis included review of medical history, and a standard ophthalmologic exam in conjunction with fundus photography, fluorescein angiography, and electroretinography in select cases. DNA was isolated from peripheral blood lymphocytes. Linkage and haplotype analyses was carried out using microsatellite markers. Mutation analysis was performed by sequencing exons and exon-intron junctions of candidate genes. Results. The affected family members manifested a wide spectrum of clinical phenotypes including exudative and nonexudative maculopathy with onset in the late fifth decade of life. Linkage analysis with markers linked to previously known maculopathy loci excluded most of them. Markers D6S1604 (Zmax of 3.18 at θ = 0), and D6S282 (Zmax of 3.36 at θ = 0) gave significant positive LOD scores localizing the disease gene to a 9-cM interval at the RDS/peripherin locus. The critical interval encompassed GUCA1A, GUCA1B and RDS/peripherin gene shown to be associated with retinal dystrophies. Mutation analysis excluded GUCA1A and GUCA1B genes and revealed a missense mutation in the RDS/peripherin gene leading to a Tyr141Cys substitution in all affected members. Conclusion. RDS mutation in codon 141 is associated with an unusual late-onset maculopathy with broad range of clinical manifestation including exudative and nonexudative features characteristic of age-related macular degeneration. A significant bias (Z~3) favoring the transmission of disease carrying haplotype and gamete is suggested by the unusually high proportion of the affected individuals among the progeny. Observations in the above family broaden the spectrum of phenotype associated with RDS/peripherin gene mutations.

Keywords: retinal degenerations: hereditary • age-related macular degeneration • degenerations/dystrophies