Association of a Novel Mutation in the Retinol Dehydrogenase 12 (RDH12) Gene With Autosomal Dominant Retinitis Pigmentosa

Objective To identify the gene causing retinitis pigmentosa (RP) in an autosomal dominant pedigree. Methods Family members with RP were studied with linkage analysis using single-nucleotide polymorphism and short tandem repeat polymorphic markers. Candidate genes in the linked region were evaluated with DNA sequencing. Results Nineteen family members had a mild form of RP. Multipoint linkage analysis of single-nucleotide polymorphism genotypes yielded a maximum nonparametric linkage score of 19.97 with markers located on chromosome 14q. LOD scores higher than 3.0 were obtained with 20 short tandem repeat polymorphic markers, and recombinants defined a 21.7-centimorgan locus on chromosome 14q. The retinol dehydrogenase 12 ( RDH12 ) gene lies within this locus and was evaluated as a candidate gene. A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects. Conclusions Heterozygous mutations in RDH12 can cause autosomal dominant RP with a late onset and relatively mild severity. This phenotype is dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis. Clinical Relevance The demonstration that mutations in a gene previously associated with recessive Leber congenital amaurosis can also cause dominant RP illustrates the wide phenotypic variability of retinal degeneration genes.