Fareeha, Zulfiqar (2006) GENETIC AND MOLECULAR BASIS OF HEREDITARY BLINDNESS. Doctoral thesis, University of the Punjab.

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The last decade witnessed a rapid progress in studies of the genetics of retinitis pigmentosa (RP) There are over 70 loci that cause photoreceptor dysfunction or degeneration in drosophila and a similar number may be expected in humans (phelan and bak, 2000). So far, thirty- nine genetic loci responsible for nonsyndromic RP have been mapped in humans. Search for new RP loci/genes is imperative far a better understanding of the genetic and molecular bases of the visual cascade. The Pakistan population provides a valuable genetic resource for studies of retinitis pigmentosa because inbred families with many affected individuals are easily available. In the present study. 65 consanguineous families with 2-5 sibships and 3-16 affected with nonysyndromic hereditary RP were enrolled Genomic DNA samples from blood samples of all the participating members of these families. The families with three or more affected were studied by linkage analysis. Genome wide scans were performed to map new RP loct and DNA sequence amylases done to fend new mutations in reported and new genes. As a result, RP phenotypes in six families linked to known RP loci. Mutational studies were carried out in two families for CNGAI and BBS2 genes. In family PKRP039 a 626- 627 del TA mutation in the CNGAL gene resulting in a predicted frame shift Ser209fs X26 was found segregating with RP. Analyses of PKRP014 revealed a novel Arg417Ter mutation in the BBS2 protein. The RP phenotype in remaining 59 families are found unlinked to any of the known RP causing loci, which support the nation that a large number loci/genes, remain undiscovered. Genome wide linkage analyses revealed two new loci causing RP in the Pakistani population. Three families with autosomal recessive RP. PKRP006, PKRP040, and PKRP143, mapped to a 14.21 cM (21.19 Mb) region on chromosome 8q11. This region harbors gene responsible for autosomal dominant retinitis pigmentosa. RP. Sequence analyses of all the coding and nocoding exons of RPI show three different mutations segregating with RP with in these families, including two single base deletions. c. 7470delA and c. 8168delA resulting in a predicted frame shift and a 4bp insertion c 4377-4378ins TGAA. All these mutations are predicted to cause premature termination of the protein. This is a first report demonstrating the alleles of RP associated nonsyndromic recessively inherited pigmentosa. A new RP cocus RP32 was mapped through the genome wide linkage analysis using the DNA sample from a multi-sibships consanguineous PKRP030 family segregating outosomal recessive RP phenotype cosegregates with polymorphic markers at Ip13.3-p21.2 defining a new locus for RP. This locus lies approximately 4.9cM (7.1Mb) from ABCA4, which is excluded from the linked region. Identification of this new locus will improve the understanding on the mechanism of vision transduction. In conclusion this study reports the enrollment of 65 families with outosomal recessive retinitis pigmentosa, identification of two new mutations in the known RP genes. Mapping of two loci responsible for recessive RP and identification of recessive alleles of RPI gene.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: hereditary blindness, tunics of eye, vascular tunic, genome wide scan, lod score, retinitis pigmentosa, loci, photoreceptor dysfunction, drosophila
Subjects: Q Science > QR Microbiology
Depositing User: Muhammad Khan Khan
Date Deposited: 27 Oct 2016 05:05
Last Modified: 27 Oct 2016 05:05

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