Sendromik olmayan otozomal resesif işitme kaybı olan beş ailede genom boyunca genotipleme analizi
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Date
2008
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Biyoteknoloji Enstitüsü
Abstract
Congenital or prelingual hearing loss occurs approximately in one case per 1000 live births. Genetic causes are responsible in 50% of cases. Additional findings are present in 30% of cases, which are referred to as having syndromic deafness. Autosomal recessive transmission occurs in 80% of hereditary deafness. To date, 27 genes, in which mutations are responsible for autosomal recessive deafness have been identified. Five families with parental consanguinity segregating autosomal recessive deafness, which have at least 3 affected individuals by profound prelingual deafness were included in this study. These families were ascertained among a larger number of families with initial findings suggesting the presence of a causative DNA change in a known deafness gene. Mutations in GJB2 were screened and found to be negative. Genomic DNA extracted by using standard phenol-chloroform method was used to genotype genomewide SNPs with microarray. Homozygous blocks flanking a known deafness gene in affected family members were considered to be evidence for the presence of a causative change in a given deafness gene. All family members were later included for microsatellite marker genotyping to determine co-segregation with the phenotype.Initial screening with genomewide SNPs suggested the presence of responsible changes in genes CDH23 (1 family), TMIE (1 family), and TMC1 (3 families). CDH23, encodes calcium dependent cell-cell adhesion glycoproteins, which is expressed in the neurosensory epithelium. The protein is thought to be involved in stereocilia organization and hair bundle formation. TMC1 encodes an ion-transport protein. The specific function of this gene is unknown but as demonstrated in the mouse, Tmc1 mRNA is expressed in hair cells of the postnatal cochlea and vestibular organs and is required for normal function of cochlear hair cells. The specific function of TMIE is unknown but Tmie is required for normal postnatal maturation of sensory hair cells in the cochlea. Mutations were screened using PCR- SSCP methods for TMC1 and CDH23 genes followed by direct sequencing. Direct DNA sequencing was performed for the TMIE gene. A missense mutation, c.1333C>T (p.R445C), was found in one family and a splice side mutation, IVS6+2 T>A, was identified in the another. In the third family, a deletion was identified which includes exons 19 and 24. In the CDH23 gene, an intronic c.3595-13C>T change was found. None of these mutations has been previously reported. The c.250C>T (p.R84W) mutation was detected in the TMIE gene in one family. This mutation has been previously described.In our study we identified causative DNA changes in five families segregating nonsyndromic autosomal recessive deafness.
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Genetik, İşitme Kaybı