Novel Mutation in the Retinol Dehydrogenase 12 (rdh12) Gene Is Associated With Retinitis Pigmentosa in a Large Autosomal Dominant Pedigree From Iowa

Abstract

Purpose: : To identify the gene causing retinitis pigmentosa (RP) in a large pedigree with an autosomal dominant pattern of disease.

Methods: : Family members with RP were studied with linkage analysis using single nucleotide polymorphism (SNP) and short tandem repeat polymorphism (STRP) genetic markers. Candidate genes in the linked region were evaluated with bidirectional DNA sequencing.

Results: : Thirty-five family members were examined and 19 were diagnosed with a mild form of RP. Eight of the 19 affected family members were studied with linkage analysis using microarrays of SNPs. Multipoint linkage analysis of SNP genotypes yielded a maximum nonparametric linkage score of 19.97 with markers located on chromosome 14q. Next, all 19 affected family members were genotyped with STRP markers on chromosome 14q. Two-point LOD scores over 3.0 were obtained with 20 STRP markers. Recombination analysis defined a 21.7 cM locus between markers D14S1018 and D14S251 on chromosome 14q. The retinol dehydrogenase 12 (RDH12) gene lies within this locus and was evaluated as a candidate gene with bi-directional DNA sequencing. A heterozygous frame-shift mutation (776delG) was detected in all affected family members and was not detected in 90 control subjects.

Conclusions: : Heterozygous mutations in RDH12 may cause autosomal dominant RP that is characterized by 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.

Keywords: genetics • retinal degenerations: hereditary • gene mapping