Genetic and Clinical Analyses of a Large Family With X-Linked Cone-Rod Degeneration

Abstract

Purpose:: Only one X-linked gene, RPGR, is currently known to cause cone / cone-rod degeneration (CD/CRD) and two additional loci (COD2 and COD4) were mapped by linkage analysis. One family with progressive cone dystrophy was previously reported to be linked to the COD2 region on Xq27. The aim of the current study was to perform a genetic and clinical evaluation of a large Israeli family with X-linked cone-rod degeneration (XLCRD).

Methods:: Clinical evaluation included detailed family history, full ophthalmologic exam, and full-field electroretinography (ERG). Haplotype and linkage analyses were performed by studying 26 microsatellite markers covering the entire X-chromosome. Mutation analysis was performed by direct sequencing of PCR products. The GO, EST, and SAGEmap databases were used to collect information regarding the function and expression pattern of genes located within the linked interval.

Results:: We recruited a large Moroccan Jewish family with XLCRD and clinically assessed six affected children. Affected individuals had varying degrees of nystagmus, their visual acuity was markedly impaired, and all had severely reduced or extinct full field ERG cone responses. Rods were also affected but to a lesser extent. Linkage analysis clearly implicated the COD2 region and excluded the remaining X-chromosome including the RPGR and COD4 regions. Aiming to identify the causative gene, we tabulated all known genes in the COD2 region and collected information regarding their expression pattern and presumed protein function. Out of the 33 genes evaluated, we considered three that are highly expressed in the retina as candidates for the disease. Two of the genes belong to a family of proteins that are speculated to be involved in axonal growth and the third gene encodes a protein with unknown function. A mutation analysis of these genes is in progress.

Conclusions:: The family presented here is the second family linked to the COD2 region and may allow identification of the causative gene.

Keywords: gene mapping • retinal degenerations: hereditary • genetics