Pakistan Research Repository


Riazuddin, Saima (2001) GENETIC AND MOLECULAR BASIS OF NONSYNDROMIC DEAFNESS. PhD thesis, University of the Punjab, Lahore.



The last decade witnessed a rapid progress in studies of the genetics of hereditary hearing impairment. Sixty nine genetic loci responsible for nonsyndromic hereditary hearing impairment have been mapped. Considering the complexity of the hearing process, it is estimated that may be as many as 500 loci/genes will be involved in the human auditory functions. Search for new deafness loci/genes is imperative for a better understanding of genetic and molecular basis of auditory functions. Recessively inherited deafness in the Pakistani population is higher than world average due to high consanguinity. This population thus provides a valuable genetic resource for studies of deafness because large families with many affected individuals are easily available. In the present study, 126 consanguineous families with 2-5 sib ships and 3-16, affected with nonsyndromic hereditary hearing loss, were enrolled. Blood samples were obtained from the affected individuals, normal siblings, their parents, grandparents if alive, and other related family members. The blood samples were processed to isolate genomic DNA. The families with 3 or more affecteds were studied by linkage analysis. Genome wide scans were performed to identify new deafness loci/genes and DNA sequence analyses were done to find new mutations in some of the previously reported loci. As a result of input into these studies, thirty-four families are found linked to DFNBI, DFNB3, DFNB4, DFNB6, DFNB7/11, DFNB8/10, DFNB9, DFNBI2/USDID, DFNBI8 DFNB23/USHIF, DFNB28 and DFNB29 and the remaining 92 families are found unlinked to any of the known deafness loci. The fact that a large number of affected individuals/families are not linked to anyone of the known genes/loci support the nation that a large number loci/genes, remain undiscovered. Further studies revealed that six families have affected individuals mutated for GJB2, the gene responsible for DFNBI. Two known mutations W77X and W24X are found segregating in these families. There are 7 families in which the affected are not deaf due to GJB2, yet they are carriers of this mutation. Four families are linked to DFNB3 locus and mutational screening of one of these family (PKSR4) led to the identification of a novel donor splice site mutation (IVS4+1G-T) in the MYO15 gene. Three families linked to DFNB4 are mutated for PDS. Two families are linked to the DFNB6 locus. Three families linked to DFNB8/10, have two novel mutations (C407R and RI09W) in TMPRSS3 gene. Only one family is linked to DFNB9 and one to DFNB28 locus. One family SR9a helped in the identification of a novel locus DFNB29. The linkage analysis studies also helped in refining the reported linkage intervals and thus facilitated the identification of the related loci. Four families are linked to DENB7/11, five families are linked to DFNBI2/USHID locus, and three families are linked to DFNB23/USHIF locus. The meiotic recombinations in families linked to the three loci (DFNB7/11, DFNBI2/USHID and DFNB23/USHIF) helped in refining the reported linkage interval from 18cM, 14cM and 20cM respectively to less than one cM. Genome wide linkage analysis studies in a large consanguineous family, PK2, led to the identification of a new locus, designated as “DFNB26” that was mapped within a 1.5 cM interval on chromosome 4q31. A maximum lod score of 8.10 at 0=0 was obtained with DS1610. There were seven unaffected family members who were also homozygous for the DFNB26 linked haplotype and thus were non-penetrant. A dominant modifier locus was mapped to a 5.6 cM region on chromosome lq24 in this family which protects the seven individuals from hearing loss. Since this is the first example of a modifier locus for hereditary hearing loss, therefore it was named as DFNMI. A maximum lod score of 4.31 was obtained for the DFNMI locus at 0=0 for DS2815. The physical mapping of DFNB26 and DFNMI was performed and the candidate genes in the linkage interval identified. Although mapping of modifiers is not unique, this is the first example of a suppresser for human deafness that has been found to completely rescue the expected loss of hearing (Riazuddin et al., Nature Genet. 2000). The identification of a modifier locus (DFNMI) of deafness has helped us understand the non-penetrance of deafness in 7 individuals in the family PK2. Identification of the genes for DFNB26 and DFNMI will reveal further insights into the genetics of deafness.

Item Type:Thesis (PhD)
Uncontrolled Keywords:Hereditary Hearing Impairment, Genetic Loci, Inherited Deafness, DNA, DFNBI, DFNB3, DFNB4, DFNB6, DFNB7/11, DFNB8/10, DFNB9, DFNBI2/USDID, DFNBI8 DFNB23/USHIF, DFNB28, DFNB29, DFNB26, DFNA1, DFNA, DFNA5, DFNA9, DFNA13, DFNA15, Genetic Mapping,
Subjects:Biological & Medical Sciences (c) > Biological Sciences(c1) > Biology (c13)
ID Code:361
Deposited By:Mr Ghulam Murtaza
Deposited On:05 Jul 2006
Last Modified:04 Oct 2007 21:00

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