Hearing Impairment , the partial or absolute inability to perceive sound is one of the most frequent sensory defect with an estimated prevalence of one in thousand (Morton and Nance, 2006). Hearing loss may result from genetic, environmental or an interaction of both factors (Nance, 2003; Morton and Nance, 2006).The phenotype spectrum of hereditary hearing loss can be divided into two groups, syndromic (30%) which is associated with other anomalies and non syndromic form (70%), having hearing loss only (Van Camp, Willems, & Smith, 1997).The present study was aimed to elucidate the molecular basis of hereditary hearing loss. For this purpose, 25 highly inbred families with history of hearing impairment were enrolled from different areas of Pakistan. After written informed consent, blood samples were collected from study participants. DNA was extracted and processed for exclusion studies of known autosomal recessive deafness loci. Deafness in five families showed linkage to DFNB3, DFNB9, DSFNB28, DFNB37 and DFNB67.In the remaining 20 families, phenotype of deafness did not segregate with the markers of any of the known loci.In the second part of the study, genome wide scan was performed on three unlinked families.A novel region DFNB87 segregating with deafness was mapped on chromosome 9 in PKDF882. The critical region of this novel locus mapped to 9q21.31-q22.2 flanked by markers D9S922 (80.31cM) and D9S1836 (96.99CM) spanning a genetic interval of 16.86cM. The newly defined linkage interval does not overlap with any of the previously reported loci on chromosome 9. The linkage interval harbors 69 genes including seven (TLE1, UBQLNI, NTRK2, GOLM1, SPINI, CSK2 and SECISBP2) potential candidate genes on the basis of their expression in both human and mouse inner ear (Peters et al., 2007; UCSC Genome Browser). To narrow down the region, 350 families segregating hereditary hearing impairment, available in CEMB DNA bank, were screened for this locus, but deafness in any family did not segregate with this new region. Localization of this novel locus reveals genetic heterogeneity of Pakistani population and has provided an insight in the molecular basis of deafness, and also is a first step towards the identification of a novel gene that is involved in normal hearing. In the third part of the study, an effort was made to define the mutation spectrum of PCDH15. Eight consanguineous Pakistani families segregating DFNB23/USH1F linked deafness underwent mutational analysis of PCDH15. Sequence variants of PCDH15 can cause syndromic deafness characterized by hearing and vision impairment (type 1 Usher syndrome; USH1F) or non-syndromic deafness (DFNB23) (Ahmed et al., 2003b).Sequence analysis of PCDH15 gene revealed eight different mutations (p.V1240LfsX2, p.R3X, p.R134G, p.L1419FfsX99, p.Y684X, p.S647X, p.D178G and p.E829KfsX12 ) in eight different families of which six were novel.
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