Mutational Analysis Of Mitochondrial DNA In Familes With Maternally Inherited Hearing Loss

The last decade has led to the identification of several mitochondrial DNA mutations associated with hearing loss. Mitochondrial 12S rRNA and tRNA^Ser(UCN) genes have been shown to be the hot spots for mutations associated with hearing loss. The A1555G, C1494T , 961insC mutations in the highly conserved decoding sites of the 12S rRNA have been identified with both aminoglycoside-induced and non-syndromic hearing loss. Four non-syndromic deafness-associated mutations:A7445G, 7472insC, T7510C and T7511C have been identified in the tRNA^Ser(UCN) gene. The first identified mtDNA mutation associated with non-syndromic deafness was mtDNA A1555G mutation. Maternal family members with A1555G mutation developed non-syndromic sensorineural hearing loss with and without aminoglycosides. In the United States, the 1555 mutation accounts for 15% of all cases of aminoglycoside-induced deafness.Later studies indicate a higher frequency of this mutation than previously expected.In the Spanish,there are 19 families with the mtDNA A1555G mutation out of a total of 70 families with sensorineural hearing loss collected. The mtDNA A1555G mutation was identified on different haplotypes. In a study that reviewed all deaf-mutes in a district of Shanghai, 21.9% had aminoglycoside-induced hearing loss, representing 167 individuals from a population of nearly half a million. So the investigation into the association between the machanism of inherited hearing loss and mitochondrial DNA mutations has great social and economical significance. In the study, we report 3 additional mtDNA mutations in 12S rRNA and tRNA^Ser(UCN) genes as the pathogenic cause of maternally transmitted non-syndromic deafness families and discuss the character of mitochondrial DNA mutations.Objective: To study the association between mtDNA mutations andmaternally transmitted non-syndromic hearing loss. To disclose mtDNA mutations which contribute to the hearing loss of these familes by directsequencing mtDNA 12SrRNA and tRNASei bovine> mouse^ xenopus laevis.Results: All samples obtained from maternal members of the familiescarried mtDNA A1555G mutation.One family also has G1007A and A1313G mutations in 12SrRNA gene.The mtDNA 1007 and 1313 positions are conservative in humam bovinenmouse> xenopus laevis. Computerized modeling shows that the mutations made the 12SrRNA secondary structure totally different,and the energy changes from -350.8Kcal/mol to -356. 6Kcal/mol (-5. 8 Kcal/mol). Another family carried G7444A mutation in COI/tRNASei(UCN) gene.The mtDNA G7444A mutation on the H-strand of mtDNA results in a read -through of the stop condon AGA of the COI message,adding three amino acids(Lys-Gln-Lys) to the C-terminal of the polypeptide.Alternatively,the G7444A mutation is adjacent to the side of 3' end endonucleolytic processing of the L-strand RNA precursor,led to a failure in the processing of the L-strand RNA precursor.Conclusions: The mtDNA A1555Gn G1007A^ A1313G mutations might relate to the pathogenesis of maternally transmitted non-syndromic deafness.Double mutations of A1555G and G7444A may play a pivotal role in the pathogenesis of hearing loss in this family with non—syndromic inherited hearing impairment.