A Common Founder Mutation of CERKL Underlies Autosomal Recessive Severe Retinal Degeneration With Early Macular Involvement in the Yemenite Jewish Population

Abstract

Purpose:: To investigate the genetic basis for retinal degeneration in the Yemenite Jewish population.

Methods:: Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic retinal degeneration was performed in an extended Yemenite Jewish family segregating autosomal recessive severe retinal degeneration with early macular involvement. Mutation screening of the underlying gene was performed by direct sequencing. Following identification of the causative mutation, it was screened for in a panel of 16 additional Yemenite Jewish probands with retinal degeneration. Patients homozygous for this mutation underwent ophthalmic evaluation, including funduscopy, visual field testing and electroretinograms.

Results:: In an extended Yemenite Jewish family segregating autosomal recessive severe retinal degeneration with early macular involvement, we found evidence for linkage to the CERKL gene. Direct sequencing reveled a novel homozygous splice-site mutation, c.238+1G>A. We used an in vitro splicing assay to demonstrate that this mutation leads to incorrect splicing. c.238+1G>A was found in four additional Yemenite Jewish families segregating retinal degeneration. The carrier frequency of this mutation in the Yemenite Jewish population is 4.4%. All chromosomes harboring the c.238+1G>A mutation share the same haplotype, thus indicating a founder effect in the Yemenite Jewish population. All patients homozygous for the c.238+1G>A mutation manifest widespread impairment of rod and cone function with early macular involvement.

Conclusions:: c.238+1G>A is the second reported mutation of the CERKL gene which underlies retinal degeneration. c.238+1G>A is a prevalent founder mutation which underlies approximately 30% of autosomal recessive retinal degeneration cases in the Yemenite Jewish population. The identification of this mutation will facilitate molecular diagnosis, carrier screening and genetic counseling in this population. c.238+1G>A is associated with an atypical retinal degeneration phenotype, involving both peripheral and central regions of the retina early-on in the disease process.

Keywords: retinal degenerations: hereditary • genetics