A survey of DNA variation of C2ORF71 in probands with progressive autosomal recessive retinal degeneration and controls.

Purpose: Mutations of C2ORF71 have recently been reported to be associated with autosomal recessive (AR) retinitis pigmentosa (RP) in humans and with visual defects in zebrafish. C2ORF71 is located on 2p23.2 and encodes a 1288-amino-acid protein of unknown function, predominately expressed in the photoreceptors. The study was conducted to determine the prevalence of mutations in C2ORF71 in a cohort of probands with AR retinal degeneration and to detect coding sequence variation in controls.

Methods: A combination of high-resolution DNA melting (HRM) analysis and automated DNA sequencing was used to screen for C2ORF71 in 286 affected unrelated individuals. Among them, 95 subjects had Leber congenital amaurosis, and 191 had AR RP. In a similar fashion, 151 European and 40 South Asian control DNAs were screened.

Results: Overall, 40 DNA sequence variants were detected, with 17 novel polymorphisms found in the control subjects (8 missense, 7 synonymous, and 2 other). Importantly, 11 novel sequence variants (6 missense and 5 synonymous) in 20 alleles were detected in the cohort of patients but not in the controls. Only one proband was a compound heterozygote but segregation analysis revealed her unaffected father to be homozygous for one of the putative mutations.

Conclusions: C2ORF71 is a highly polymorphic gene (average heterozygosity of coding region in controls: 2.118 × 10(-3)) with many rare variants that confound mutation detection. Further analysis will determine the spectrum of retinal disease caused by mutations in C2ORF71 and distinguish true pathogenic alleles from the high background of polymorphism elucidating the role of this rare cause of RP in the visual process.