A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype

Abstract

Purpose: : To identify the genetic defects in a family which exhibited variable retinal phenotypes, including Leber congenital amaurosis (LCA) in the proband, early-onset severe retinal dystrophy (EOSRD) in two cousins and retinitis pigmentosa (RP) in a distant family member.

Methods: : DNA samples of the affected family members were genotyped with genome-wide SNP microarrays. The genetic defects were localized by linkage analysis and homozygosity mapping. Patients were ophthalmologically examined.

Results: : Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655G>A founder mutation and a novel nonsense mutation (c.451C>T, p.Arg151X). Clinical evaluations in the proband showed nystagmus, hyperopia and decreased visual acuity from birth (20/250). Scotopic ERG responses were measurable (although minimal) in the two cousins with EOSRD at the age of 2 years. In one of these patients the visual acuity reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA revealed mutant splice forms in which either exon 7 or exons 7 and 8 were skipped. Furthermore, homozygosity mapping and mutation analysis in a distant family member affected by RP revealed a homozygous mutation p.Leu394fs in MERTK. This mutation is heterozygously present in the patient with LCA, and absent in the two milder affected cousins.

Conclusions: : A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. Subsequent restoration of the open reading frame may explain the less severe phenotype observed in two cousins. An additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband.

Keywords: retinal degenerations: hereditary • gene modifiers