טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentAbbasi Anan
SubjectIdentifying the Genetic Basis for Hereditary Retinal
Degeneration in the Jewish and Arab Populations
of Israel
DepartmentDepartment of Medicine
Supervisors Professor Tamar Ben-Yosef
Professor Emeritus Ido Perlman
Clinical Professor Hanna Garzozi
Full Thesis textFull thesis text - English Version


Abstract

The Israeli population is very unique in that it consists of a variety of ethnic groups. Analysis of a large number of families, of different origins, allows us to find mutations that are prevalent in different populations. Hereditary retinal degenerations (HRD) are a clinically and genetically heterogeneous group of diseases. Retinitis pigmentosa (RP), a relatively less severe form of HRD, is the most common form, with a prevalence of 1:4000 in different populations. In most patients, the disease is limited to the eye, and can be inherited as autosomal recessive, autosomal dominant, X-linked, Mitochondrial or digenic patterns of inheritance. Mutations of the TULP1 gene cause retinal degeneration in both humans and mice. To date, 22 distinct pathogenic mutations of TULP1 have been reported in patients with LCA or RP. In my study I found a novel splice-site mutation of TULP1, c.1495+2_1495+3insT, underlying severe early-onset RP in a consanguineous Israeli Muslim Arab family.

Marked genetic heterogeneity of HRD, might appear even within highly inbred families. For example, we found allelic heterogeneity in a family where affected individuals were compound heterozygotes for two different mutations of the CRB1 gene, p.G1103R and c.4121_4130del. In another family we found evidence for locus heterogeneity. A novel homozygous mutation of RDH12, p.A126V, was found in only 14 of 17 affected individuals in this family. Our data indicate that in the other five affected individuals the disease is caused by a different gene/s.

In an extended Yemenite Jewish family, we found evidence for a homozygous splice-site mutation in the CERKL gene, 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 the Yemenite Jewish population.

I found linkage to the RDS/Peripherin gene in an Ashkenazi Jewish non-consanguineous family with AD slow degenerating RP. All affected individuals were heterozygotes for two changes on the same allele in the coding sequence of exon 2: A reported missense mutation (CCT>CTT) leading to p.P216L and an unreported sequence change (AGC>ACC) leading to p.S217T. Further analysis is required to determine if RP in this family is caused by p.P216L alone or by the combination of both changes.

Overall, 13 families with hereditary retinal degeneration were studied as part of this work. In 5 out of them the genetic cause was found.