NRL S50T mutation and the importance of 'founder effects' in inherited retinal dystrophies

The aim of this work was to identify NRL mutations in a panel of 200 autoso mal dominant retinitis pigmentosa (adRP) families. All samples were subject ed to heteroduplex analysis of the three exons of the NRL gene, and Hphl re striction digest analysis of exon 2 (to identify the S50T mutation). Famili es found to have the S50T mutation, and six additional larger pedigrees (wh ich had previously been excluded from the other nine adRP loci) underwent l inkage analysis using polymorphic markers located in the region of 14q11. H phl restriction analysis followed by direct sequencing of the amplified NRL exon 2 product demonstrated the presence of the NRL S50T sequence change i n three adRP families. Comparison of marker haplotypes in affected individu als from these families with those of affected members of the original 14q1 1 linked family revealed a common disease haplotype for markers within the adRP locus. Recombination events observed in these families define an adRP critical interval of 14.9 cM between D13S72 and D14S1041. Linkage analysis enabled all six of the larger adRP pedigrees to be excluded from the 14q11 locus. The NRL S50T mutation represents another example of a 'founder effec t' in a dominantly inherited retinal dystrophy. Identification of such 'fou nder effects' may greatly simplify diagnostic genetic screening and lead to better prognostic counselling. The exclusion of several adRP families from all ten adRP loci indicates that at least one further adRP locus remains t o be found.