New loci for autosomal recessive retinitis pigmentosa and macular degeneration

Abstract

Abstract: : Purpose:Retinitis pigmentosa (RP) are hereditary retinal dystrophies characterized by progressive loss of peripheral vision and night blindness, in opposition with macular degeneration (MD) for which central and photopic vision is altered. Genetic heterogeneity is important for RP. A survey of mutation screening reports in large series of patients indicates that the frequency of mutations for the 17 cloned genes in autosomal recessive (ar) RP varies from 17 to 24 % suggesting that other genes have to be identified. The goal of our study is to map, by linkage analysis, the genes responsible for the disease in two consanguinous ar pedigrees : one presenting RP, the second with juvenile MD, phenotype for which only ABCA4 mutations have been described. Methods:Full clinical examination and pedigree data were collected in accordance with Helsinski declaration. DNAs were extracted with a salting out procedure. Candidate genes were tested by linkage analysis using microsatellite markers in the 2 families. Hypothetising monogenic pathologies, two point LOD–scores were generated with the Linkage package version 5.2 (frequency of 0.00001 for the disease allele, penetrance 1). Genome–wide linkage analysis at 10 cM resolution was performed in collaboration with the Centre National de Genotypage (Paris, France).Additionnal markers were selected from Nature 1995. Results:For both families, known genes and loci were excluded and genome–wide linkage analysis was done to localize the mutated gene. For the RP family, an single homozygote intervalle spanning 8 cM on the short arm of chromosome 7 was validated with 5 markers (Z_max=1.98 at theta zero). For the MD pedigree, two markers define an homozygote intervalle of 1 cM on chromosome 4 (Z=1.64 at theta zero) included in a region of 4 cM linked to the pathology (4 markers). Conclusions:Additional markers will be tested to confirme the refination of intervalle homozygote by filiation in the MD family. Candidate genes belonging to the defined intervalle are currently under investigation.

Keywords: gene mapping • retinitis • linkage analysis