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Title of Thesis

Jamil Ahmad
Institute/University/Department Details
University of the Punjab
Molecular Biology
Number of Pages
Keywords (Extracted from title, table of contents and abstract of thesis)
deafness, pakistan, genetics of deafness, hearing impairment, locus dfnb-48, pcdh15

Deafness is described as partial or complete hearing impairment and is one of the most prevalent sensory defects in humans. Deafness is an etiologically heterogeneous trait with many known genetic and environmental causes. It is estimated that at least 50% of the cases are due to genetic factors (Baldwin et al., 1995). Hereditary hearing loss may be syndromic or nonsyndromic, about 30% of deafness cases are syndromic, while 70% is nonsyndromic. It is estimated that the prevalence of profound bilateral hearing loss is 1.6 per 1000 in Pakistan and 70% of hearing loss arises in consanguineous -families a(Elahi. et al., 1998, Jaber et al.. 1998). The main pattern of inheritance of deafness in Pakistani population is autosomal recessive and to date more than 59 loci and 21 genes have been identified for nonsyndromic recessive deafness.

Fifty consanguineous families from different cities of Pakistan were enrolled for the identification of new gene/locus involved in deafness. All these families showed recessive mode of inheritance. Out of 50 families, preference was given to those 25 families that had three or more affected individuals. Written informed consents were obtained, blood samples were collected and processed for DNA extraction. All these families were analyzed for linkage to known recessive deafness loci. For each deafness locus, at least three STR markers were genotyped by using ABI Prism 3100 genetic analyzer, and haplotypes were constructed to determine, if a family was linked or unlinked to a already known locus.

Two families were found linked to DFNB3, one family to DFNB4, one to DFNB7/Bll, two families to DFNB8/B10, one to DFNBI2, and three families showed linkage to DFNB23/USHIF DFNB23 and USHIF are overlapping loci and PCDH15 gene. is responsible for both the phenotypes. On the basis of type of mutations,. a genotype-phenotype correlation was performed between mutant alleles of PCDH15. The results of genotype-phenotype correlation suggest that missense mutations in PCDH15 cause DFNB23 (nonsyndromic deafness), while severe mutation (splice site, nonsense) in PCDH 15 causes USHI F (syndromic deafness).

A genome-wide scan comprising 388 microsatellite markers covering the whole human genome with an average resolution of 10 cM apart was carried out. As a consequence, a new recessive deafness locus DFNB48 was mapped to chromosome 15q23-q25.1 in five large consanguineous Pakistani families (PKDF245, PKDF270, PKDF203, PKDF356 and PKDF232). Initial localization of this locus was in an approximately 7 cM interval on chromosome 15q23-q25.1. DFNB48 is responsible for approximately 1.5% nonsyndromic congenital profound hearing loss among families that have been ascertained in Pakistan. The identification of this novel nonsyndromic recessive deafness locus demonstrates a high degree of locus heterogeneity for hearing impairment; particularly in the Pakistani population.

The DFNB48 critical interval is located in a gene rich region of chromosome 15 (UCSC Genome Bioinformatics). Some of the genes present in DFNB48 interval are interesting candidates for deafness phenotype. The genes present within the DFNB48 region are being studied by screening for mutations in all the reported five families. Genes KIAA1055, KIAA1199, CIB2, CHR150RF22, and PTPN9 have been sequenced but no mutation has been detected in any of the five candidate genes. Given the functional and structural diversity of ‚€œdeafness genes‚€Ě and the variety of proteins that they encode, candidate gene mutation analysis of DFNB48 will need to be comprehensive.

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5162.67 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
357.27 KB
2 1 Introduction 1
114.77 KB
3 2 Review Of Literature 5
1352.71 KB
  2.1 Auditory System 7
  2.2 Genetics Of Deafness 24
4 3 Materials & Methods 48
751.56 KB
  3.1 Enrollment Of Families 49
  3.2 Clinical Studies Of Enrolled Families 63
5 4 Results
1894.08 KB
  4.1 Linkage Analyses Studies For Known Recessive Deafness Loci And Mapping Of A New Deafness Locus Dfnb-48 70
  4.2 Genotype Phenotype Correlation Between Pcdh15 Multan Alleles 102
6 5 Discussion 113
292.06 KB
  5.1 Publications Of The Author 124
7 6 References 125
379.22 KB