Search

X linked progressive cone-rod dystrophy (COD) is a retinal disease primarily affecting the cone photoreceptors. The disease is genetically heterogeneous and two loci, COD 1 (Xp21.1-11.4) and COD2 (Xq27.2-28), have [...]

Usher syndrome is a group of autosomal recessive disorders that includes retinitis pigmentosa (RP) with hearing loss. Usher syndrome type II is defined as moderate to severe hearing loss with RP. The USH2A gene at 1q41 has been isolated and characterised. In 1993, a large Usher II family affected with a mild form of RP was found to be unlinked to 1q41 markers. Subsequent linkage studies of families in our Usher series identified several type II families unlinked to USH2A and USH3 on 3q25. After a second unlinked family with many affected members and a mild retinal phenotype was discovered, a genome search using these two large families showed another Usher II locus on 5q (two point lod = 3.1 at D5S484). To date, we have identified nine unrelated 5q linked families (maximum combined multipoint lod = 5.86) as well as three Usher II families that show no significant linkage to any known Usher loci. Haplotype analysis of 5q markers indicates that the new locus is flanked by D5S428 and D5S433. Review of ophthalmological data suggests that RP symptoms are milder in 5q linked families; the RP is often not diagnosed until patients near their third decade. Enamel hypoplasia and severe, very early onset RP were observed in two of the three unlinked families; dental anomalies have not been previously described as a feature of Usher type II.

The X-linked form of retinitis pigmentosa (XLRP) is a severe disease of the retina, characterised by night blindness and visual field constriction in a degenerative process, culminating with complete loss of sight within the third decade of life. Genetic mapping studies have identified two major loci for XLRP:RP3(70%–75% of XLRP) andRP2(20%–25% of XLRP). TheRPGR(retinitis pigmentosa GTPase regulator) gene has been cloned within the RP3 genomic interval and it has been shown that 10%–20% of XLRP families have mutations in this gene. Here, we describe a single-strand conformational polymorphism-based mutation screening ofRPGRin a pool of 29 XLRP families for which the disease segregates with theRP3locus, in order to investigate the proportion ofRP3families withRPGRmutations and to relate the results to previous reports. Five different new mutations have been identified: two splice site mutations for exon 1 and three frameshift mutations in exons 7, 10 and 11. The percentage ofRPGRmutations identified is 17% (5/29) in our genetically well-defined population. This figure is comparable to the percentage ofRP2gene mutations that we have detected in our entire XLRP patient pool (10%–15%). A correlation ofRPGRmutations with phenotype in the families described in this study and the biochemical characterisation of reported mutations may provide insights into the function of the protein.