Molecular Epidemiology Investigation Of Common Deafness Genes In Chinese Northwest

Hearing loss is the most prevalent sensory deficit of childhood, affecting about 1 in 1,000 children. About 60% of congenital hearing impairment cases are due to genetic defects. Over the part 10 years, As auditory genes and deafness-associated mutations are discovered at a rapid rate.Exciting opportunities have arisen to uncover the molecular mechanisms underlying hearing and hearing impairment. Since the first deafness gene was cloned in 1995, 39 genes for non-syndromic hearing loss have been identified. Since the Chinese constitute approximately one fifth of the global population, the frequency of deafness gene in the population has important implications for understanding worldwide causes of genetic deafness.This study used the Chinese Northwest genetic resource to investigate the molecular epidemiology of common deafness genes in Chinese Northwest sporadic hearing loss cases,The purpose of present study is to investigate the mechanism of deafness associated with common genes and provide some theory and suggesting for preventing and curing this kind of hearing loss. This study addressed the molecular epidemiology of GJB2 and SLC26A4 gene using Chinese sporadic hearing impaired cases , To explore the incidence of the mitochondrial 12S ribosomal RNA A1555G mutation in Chinese northwest population with non-syndromic sensorineural hearing loss, and to assess the clinical value for this molecular diagnosis in Chinese population.We carried out our research as the following three parts. Chapter one: Study of mitochondrial DNA A1555G mutation in Chinese Northwest population with non-syndromic sensorineural deafness.Hearing loss involves both genetic and environmental factors. Recent studies have identified the mtDNA A1555G homoplasmic mutation in mitochondrial DNA 12SrRNA gene region may play a pivotal role in the pathogenesis of hearing loss,it is has been associated with aminoglycoside-induced deafness(AAID).We collected blood samples and clinical data which 593 patients with non-syndromic sensorineural hearing loss in Northwest of China,and screened the mitochondrial 12S rRNA by PCR-RFLP and direct sequence. Our purpose is To estimated the frequency of mtDNA A1555G homoplasmic mutation in subjects with sporadic non-syndromic deafness and patients of aminoglycoside-induced deafness, and hope that a characterization of its molecular basis might provide a molecular and cellular understanding of aminoglycoside-induced deafness. Among 593 cases with hearing loss,we showed that the frequency of the A1555G mutation is 9.27% (55/593) in this Chinese Northwest population with non-syndromic deafness. 46 individuals from 207 patients with aminoglycoside antibiotic-induced deafness have homoplasmic mtDNA 12SrRNA A1555G mutation,furthermore,this mutation was found in 9 individuals from 386 patients without aminoglycoside antibiotic treatment. It is obvious that the mtDNA A1555G mutation has a high incidence in this region.This finding implies that genetic susceptibility to the ototoxic effects of aminoglycosides can be diagnosed and deafness can be prevented in maternal relatives by avoiding the use of these antibiotics. Thus screening for mtDNA 12SrRNAA1555G mutation is useful to molecular diagnosis for AAID.Chapter two: moleculae epidemiology of GJB2 gene in Chinese Northwest population with prelingual non-syndromic sensorineural hearing impairmentGJB2 gene encoding gap junction beta 2 protein (connexin 26) which constitute a major system of intercellular communication important in the exchange of electrolytes, second messengers and metabolites. Mutations in GJB2 are responsible for approximately one third of sporadic of congenital deafness and half of autosomal recessive non-syndromic hearing loss. The GJB2 carrier frequency of prelingual non-syndromic sensorineural hearing impairment in Chinese northwest populations is not known. This study addressed the molecular epidemiology of GJB2 gene using Chinese sporadic hearing impaired cases, Our aims were To investigate the incidence of the GJB2 gene in this region, and to evaluate the role of the GJB2 gene in cases with moderate to profound prelingual non-syndromic sensorineural hearing impairment,To determine whether GJB2 mutations are an important cause of deafness in Chinese. We conducted mutation screening of GJB2 for 584 individuals with prelingual non-syndromic deafness. Nineteen different variants of GJB2 were found, four polymorphisms were showed in all among 584 patients cases, the pathogenic mutations of were confirm 131 individuals in these patients (131/584), 235delC mutation was detected in 41 patients.Mutation 235delC is the most frequent mutation for sensorineural deafness. These results confirmed that mutations in GJB2 are a major cause of prelingual non-syndromic sensorineural hearing impairment in the Chinese northwest population. It appears from our limited data and reports from other East Asians that The 235delC mutation is the most prevalent mutation found in the Chinese deaf population. Identification of 235delC and other mutations in the GJB2 gene should facilitate molecular diagnosis.Chapter three: Moleculae epidemiology study of SLC26A4 gene in Chinese Northwest population with nonsyndromic sensorineural deafnessEnlarged vestibular aqueduct (EVA) is the most common radiological malformation of the cochlear in deaf patients, Non-syndromic Sensorineural hearing loss associated with Enlarged vestibular aqueduct been call larged vestibular aqueduct syndrome(LVAS) , The main clinical characteristics of LVAS were: early hearing loss, fluctuation in terms of during deafness evolution, By some estimates, the this disorder may account for upwards of 10% of hereditary deafness.Recente study disorder that LVAS be associated with mutations of the SLC26A4 (PDS) gene. SLC26A4 gene encodes a transmembrane protein designated pendrin. The purpose of the study is to elucidate the mutation spectrum of SLC26A4 among patients with non-syndromic Sensorineural hearing loss in Chinese northwest ,And to explore the most common mutations.Common mutations of SLC26A4 were screened in 593 patients with non-syndromic sensorineural hearing impairment.This study disclosed that high prevalence of certain SLC26A4 mutations in this region, the SLC26A4 mutation have special spectrum in these population, nine mutations were detected in 593 patients, we confirmed that IVS7-2A→G arose from a common ancestor, this study revealed that might largely facilitate mutation screening and genetic counseling in these deaf population.