To evaluate the involvement of NR2E3 in inherited retinal degenerative diseases in the Israeli and Palestinian populations and to study phenotypic variability in patients who are homozygous for the same mutation. Methods: Patients from 35 families underwent clinical evaluation, including a full ophthalmologic examination and electroretinography. Genetic analyses included direct sequencing of polymerase chain reaction products and haplotype reconstruction. Results: We recruited 6 consanguineous Muslim families and 2 Jewish families with enhanced Scone syndrome. Patients from 4 of the Muslim families were homozygous for the same NR2E3 mutation, c.119-2AϾC, but showed considerable variability in fundus appearance and retinal function, even among patients of comparable ages. Both Jewish patients were compound heterozygotes for the c.932GϾA mutation in combination with c.194-202del9bp or a novel splice-site mutation, c.747ϩ1GϾC. Homozygosity analysis in 27 consanguineous families with retinitis pigmentosa revealed a homozygous mutation, c.932GϾA, in 2 families. The electroretinographic responses in these patients were compatible with retinitis pigmentosa and did not show the characteristic enhanced Scone syndrome pattern. Conclusion: Our results demonstrate the involvement of NR2E3 in enhanced Scone syndrome and retinitis pigmentosa phenotypes in our populations. Clinical Relevance: Patients with NR2E3 mutations may manifest variable phenotypes. Moreover, patients who are homozygous for the same NR2E3 mutation have variable expression of retinal disease, suggesting the involvement of modifier genes.

Type 2 Usher syndrome (USH2) is a recessively inherited disorder, characterized by the combination of early onset, moderate-to-severe, sensorineural hearing loss, and vision impairment due to retinitis pigmentosa. From 74% to 90% of USH2 cases are caused by mutations of the USH2A gene. USH2A is composed of 72 exons, encoding for usherin, an extracellular matrix protein, which plays an important role in the development and maintenance of neurosensory cells in both retina and cochlea. To date, over 70 pathogenic mutations of USH2A have been reported in individuals of various ethnicities. Many of these mutations are rare private mutations segregating in single families. The aim of the current work was to investigate the genetic basis for USH2 among Jews of various origins. We found that four USH2A mutations (c.239-240insGTAC, c.1000C>T, c.2209C>T, and c.12067-2A>G) account for 64% of mutant alleles underlying USH2 in Jewish families of non-Ashkenazi descent. Considering the very large size of the USH2A gene and the high number of mutations detected in USH2 patients worldwide, our findings have significant implications for genetic counseling and carrier screening in various Jewish populations.

These data suggest that Pax6, a highly conserved gene, can maintain evolutionarily conserved variability at the protein level by alternative splicing and initiation mechanisms, allowing it to perform multiple functions. The variability in the length of the paired domain suggests that the different Pax6 isoforms activate different sets of genes.

These data, taken together with our previously reported electrophysiological data, contribute to our understanding of the retinal maturation processes of this widely-used animal model.