Mutations of a Novel Gene, C2ORF71, Cause Autosomal Recessive Retinitis Pigmentosa

Abstract

Purpose: : To identify the cause of nonsyndromic autosomal recessive retinitis pigmentosa (arRP), in families from Israel and the Netherlands.

Methods: : Whole-genome homozygosity mapping was conducted in two families segregating arRP. Haplotype analysis with microsatellite repeat markers linked to the identified locus was conducted in additional families. Candidate genes located within this locus were screened for mutations by direct sequencing. Patients who were homozygous for the identified mutations underwent ophthalmic evaluation, including funduscopy and electroretinography (ERG).

Results: : A shared homozygous region on chromosome 2p23.3-22.3 was identified in two families. This interval of 4.8 Mb defined a new RP locus. A missense mutation in one of the genes residing in this interval, C2ORF71, has recently been reported to be associated with RP. This novel gene harbors two exons and encodes a putative protein of 1288 amino acids. Mutation analysis of C2ORF71 detected a nonsense mutation (c.556C>T; p.Q186X) segregating with RP in one Israeli family, and a 1-bp deletion (c.946delA; p.N316MfsX5) in a Dutch family. Haplotype analysis revealed co-segregation of a C2ORF71-linked haplotype with arRP in a second Israeli family. In this family, a 13-bp deletion (c.2756_2768del; p.K919TfsX) was identified. Mutations in C2ORF71 are associated with a typical RP phenotype, including poor night vision and peripheral field loss, typical retinal bone spicule-type pigment deposits and pale appearance of the optic disk, and markedly reduced or completely extinct ERGs.

Conclusions: : Truncating mutations of C2ORF71 were identified in three unrelated families, thereby confirming the involvement of this novel gene in the etiology of arRP.

Keywords: retinal degenerations: hereditary • genetics • mutations