טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentBenayoun Liat
SubjectIdentifying the Genetic Basis for Hereditary Retinal
Degeneration in the Israeli Population
DepartmentDepartment of Medicine
Supervisors Professor Stavit Shalev
Professor Tamar Ben-Yosef
Full Thesis text - in Hebrew Full thesis text - Hebrew Version


Abstract

Human retinal dystrophies and dysfunctions are a common group of inherited retinal diseases in which the retina degenerates, leading to either partial or complete blindness. Retinitis Pigmentosa (RP), the most common form of hereditary retinal degeneration, is genetically heterogeneous disorder. To date, over 40 genes and loci have been identified in the etiology of nonsyndromic RP. However, in more than 50% of RP patients, the underlying genes are yet to be found.

Over 30 forms of syndromic RP have been described; one of them is Abetalipoproteinemia (ABL). ABL is a rare autosomal recessive metabolic disorder, characterized by the absence of plasma apolipoprotein B-containing lipoproteins and very low levels of plasma triglycerides and cholesterol. ABL is caused by mutations of the MTP gene, encoding microsomal triglyceride transfer protein. We investigated the genetic basis for ABL in a cohort of Israeli families. In Ashkenazi Jewish patients we identified a conserved haplotype and a common MTP founder mutation, p.G865X, with a carrier frequency of 1:131 in this population. We also report the first case of ABL and additional abnormalities in a Muslim Arab patient, due to a homozygous contiguous gene deletion of approximately 481 Kb, including MTP and eight other genes.

Using Haplotype analysis for all known genes and loci underlying autosomal recessive nonsyndromic RP and Leber's congenital amaurosis (LCA), we found evidence for linkage to the RDH12 gene, encoding Retinal Dehydrogenase 12 protein, in a large consanguineous Arab-Muslim family from Northern Israel segregating autosomal recessive childhood-onset severe RP. Direct sequencing revealed a novel homozygous missense mutation, p.A126V, as the major causative mutation in this family. The carrier frequency of this mutation in the Arab-Muslim population from Northern Israel was 0.62%. Interestingly, the RDH12 mutation did not co-segregate with the phenotype in six affected family members from three family branches. In one family branch we found evidence for linkage to the RP25 locus by using haplotype analysis, while in two other branches of the family, we identified a shared homozygous region spanning 3.5Mb at the 3p22.3-22.1 chromosomal region by using whole-genome SNP's analysis. These results were consistent with the hypothesis that in the same family at least three genes are involved in the visual impairment.

The research described here will have important implications and great value for genetic counseling, carrier screening, molecular diagnosis and better understanding of the pathophysiology of hereditary retinal degeneration in various ethnic populations.