X-Linked Recessive Mutations in Simplex Males With Retinitis Pigmentosa

Abstract

Purpose: : To determine the proportion of simplex males with retinitis pigmentosa (RP) who have mutations in the X-chromosome genes RP2 and RPGR.

Methods: : A total of 173 simplex males with a diagnosis of RP were examined, and blood was collected for DNA analysis. Simplex males were defined as subjects who had no affected male family members. Patients with a history of parental consanguinity were excluded. The diagnosis of RP was made by clinical examination, visual fields, and/or electroretinography. The subjects were screened for mutations in RP2 and RPGR using PCR and direct sequencing. Missense, nonsense, and splice site mutations as well as deletions were considered causative if they had been previously reported in the literature as mutations, if they were not previously published as polymorphisms, or if they were not found in a group of 96 normal controls.

Results: : Twenty-eight mutations in X-chromosome genes were identified, including 4 in RP2 and 24 in RPGR. Of the RPGR mutations, 12 were located in the mutation hotspot region ORF15. We found an overall mutation rate of 16.2%, with 13.9% of males carrying mutations in RPGR, and 2.3% in RP2. Mutations in the hotspot region ORF15 were identified in 6.9% of our cohort. Previous reports of mutation rates in smaller cohorts of 30-55 simplex males range from 13.3-32%^1,2,3, which is consistent with this study.

Conclusions: : This study represents the largest cohort of simplex males with RP screened to date for the RP2 and RPGR genes and demonstrates the important contribution of X-linked mutations to hereditary retinal degenerations, and in particular, as a cause of simplex RP.¹Sharon D, Sandberg MA, Rabe VW, et al. Am J Hum Genet 2003; 73:1131-46.²Breuer DK, Yashar BM, Filippova E, et al. Am J Hum Genet 2002; 70:1545-54.³Pelletier V, Jambou M, Delphin N, et al. Hum Mutat 2007; 28:81-91.

Keywords: retinal degenerations: hereditary • gene screening