טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAuslender Noa
SubjectThe Genetic Basis for Syndromic and Non-syndromic Retinitis
Pigmentosa in the Israeli Population
DepartmentDepartment of Medicine
Supervisor Professor Tamar Ben-Yosef
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


Abstract

The Israeli population consists of a variety of sub-populations such as Jews, Christians, Muslims, Druze and other ethnic groups. Each of these groups holds a unique genetic structure, and therefore has its own unique set of mutations. In this work we focused on the genetic basis for syndromic and non-syndromic Retinitis Pigmentosa (RP) in Jewish families of different origins. RP is the most common form of hereditary retinal degeneration, characterized by night-blindness and gradual loss of the visual field due to degeneration of the photoreceptors, constriction of retinal arterioles and optic disc pallor, with prevalence of 20-40;100,000 in different populations. To date, about 50 loci and genes have been implicated in non-syndromic RP, and at least 30 have been implicated in autosomal recessive RP, one of which is CERKL, encoding a novel ceramide kinase-like protein. Using haplotype analysis we found evidence for linkage to the CERKL gene in an extended Yemenite Jewish family segregating autosomal recessive severe retinal degeneration with early macular involvement. Direct sequencing revealed a homozygous splice-site mutation, c.238+1G>A. This mutation was found to underlie approximately 30% of retinal degeneration cases in the Yemenite Jewish population, with a carrier frequency of 4.4%. All chromosomes harboring the c.238+1G>A mutation share the same haplotype, thus indicating a founder effect in this population. Patients homozygous for c.238+1G>A share an unusual retinal phenotype, including disturbances in both peripheral and central vision.

RP can also appear as a part of various syndromes, one of which is Usher Syndrome (USH), present in over 50% of deaf-blind patients. USH is characterized by RP, bilateral hearing loss, and impairments in the vestibular function. USH is genetically and clinically heterogeneous. The most common subtype of USH is USH2A, caused by mutations is the gene USH2A, encoding the protein Usherin, and accounting for 70%-85% of all USH cases. Using haplotype analysis we found evidence for linkage to USH2A in five Jewish families of non-Ashkenazi origin. Direct sequencing of the USH2A gene revealed five mutations in these families: p.T80fs, p.R334W, p.R737X, which have been found previously in Jewish patients of non-Ashkenazi origin, and two novel mutations, p.G1840V and c.12067-2A>G. Conserved haplotypes were found on all chromosomes harboring the p.T80fs, p.R334W, p.R737X and c.12067-2A>G mutations. Therefore, we suggest that these four USH2A mutations are founder mutations in different non-Ashkenazi Jewish populations.

We hope that the identification of these CERKL and USH2A mutations will facilitate molecular diagnosis, carrier screening and genetic counseling in the relevant populations.