Abstract
Purpose: :
Isolated populations are often characterized by the existence of founder mutations that are population-specific. The North African Jewish community has a long history, complicated by a number of immigration waves as well as large persecutions that dramatically affected population size. As part of our study of the genetics of inherited retinal diseases in Israel, we identified a relatively large number of retinal degeneration patients from North African Jewish descent. The aim of the current study was to identify the genetic cause of retinal disease in patients from North African Jewish origin who suffer from autosomal recessive (AR) Leber congenital amaurosis (LCA) or early-onset retinitis pigmentosa (RP).
Methods: :
Fifty-three families with the diagnosis of AR-LCA or ARRP were recruited for the study. Blood samples were drawn from family members and genomic DNA was analyzed by mutation detection microarray analysis, direct sequencing, and 10K whole genome single nucleotide polymorphism (SNP) markers.
Results: :
We identified a homozygous splice site mutation, c.95-2A>T (IVS2-2A>T), in the RPE65 gene in seven families, all originated from the North African Jewish population. All affected individuals were homozygote for this mutation and suffered from early-onset and severe retinal degeneration diagnosed clinically as either LCA or early-onset RP. The mutation was not found in North African Jewish patients with ARRP nor was it found in LCA or RP patients from other ethnic origins. The findings suggest a founder LCA/early RP mutation that is specific to the North African Jewish population. Haplotype analysis using SNP markers in the vicinity of RPE65 revealed a shared homozygous region in seven patients. Using the DMLE program, the age of the founder mutation was estimated as 100-130 generations ago. To evaluate the carrier frequency of the IVS2-2A>T mutation, we screened 179 origin-matched control individuals and identified two carriers (estimated carrier frequency of ~1.1%).
Conclusions: :
The age of the RPE65 founder mutation suggests that it originated around the establishment of the Jewish community in North Africa (about 2000-2600 years ago) and is currently the most common identified cause of early retinal degeneration in this population. The results of this study will allow identification of carriers in the community and provide the basis for better genetic counseling and disease prevention. Perhaps more importantly, the 21 patients we have identified who are homozygote for this RPE65 mutation may be candidates for the novel RPE65 gene therapy now available.
Keywords: genetics • retinal degenerations: hereditary • mutations