A Missense Mutation in the Dehydrodolichyl Diphosphate Synthase (DHDDS) Gene is Associated with Autosomal Recessive Retinitis Pigmentosa in Ashkenazi Jews

Abstract

Purpose: : Retinitis pigmentosa (RP) is the most common inherited retinal degeneration with a prevalence of 1:4,000. The disease is heterogeneous and 35 loci are currently linked to autosomal recessive RP (arRP). Several newly identified genes were not a priori considered candidates for RP and were identified by whole genome linkage analysis. Our aim is to identify new arRP-associated genes using homozygosity mapping.

Methods: : All patients were evaluated clinically and with visual function studies. Genomic DNA was tested for mutations in the DHDDS gene by sequencing and enzymatic restriction and for homozygosity using the Affymetrix whole genome 250K and 6.0 single nucleotide polymorphism (SNP) arrays.

Results: : Using homozygosity mapping we identified a shared 3.7Mb homozygous region on chromosome 1p35.3-p36.11 in Ashkenazi Jewish (AJ) patients with arRP who belong to 2 unrelated families. Sequence analysis revealed a homozygous missense mutation, c.124A>G (p.K42E), in the DHDDS gene encoding the dehydrodolichyl diphosphate synthase in 5 affected individuals of the 2 above-mentioned families, as well as in 14 other AJ patients with RP of 12 unrelated families. The haplotype in these 2 families was found to be identical, suggesting a founder effect. The mutation was not identified in an additional set of 107 AJ patients with RP, 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other origins. The mutation was found heterozygously in 1/322 ethnically-matched normal controls. The statistical difference between the cohort of patients and controls was highly significant (p<0.0001). The affected amino acid (K42) is located immediately after the diphosphate binding site of the enzyme. Clinical phenotype of patients homozygous for the c.124A>G mutation was within the spectrum associated with arRP.

Conclusions: : DHDDS is a key enzyme in the pathway of dolichol which plays an important role in N-glycosylation of many glycoproteins, including rhodopsin. Previous studies showed that distruption of this pathway in the frog eye results in an RP-like phenotype. Our results support a pivotal role of DHDDS in retinal function and might allow for new therapeutic interventions for RP.

Keywords: genetics • retinal degenerations: hereditary • gene screening