MUTATION IN THE MITOCHONDRIAL 12S RIBOSOMAL-RNA GENE IN 2 FAMILIES FROM MONGOLIA WITH MATRILINEAL AMINOGLYCOSIDE OTOTOXICITY

Irreversible hearing loss is a catastrophic complication of treatment with aminoglycoside antibiotics such as streptomycin, gentamycin, and kanamycin. Many kindreds showing a matrilineal pattern of inheritance of this trait have been described in China where the widespread use of aminoglycoside antibiotics accounts for approximately 25% of profound deafness in some districts. Because of the characteristic inheritance pattern, mitochondrial DNA (mtDNA) mutations were postulated to be th e cause of the deafness in these pedigrees. In 1993 it was shown that an A to G substitution at base pair 1555 of the mitochondrial 12S ribo somal RNA gene was the only mutation common to all the families with a minoglycoside ototoxicity. We ascertained three Mongolian pedigrees fr om the School for the Deaf and Blind in Ulaanbaatar, all of which cont ained multiple affected subjects with streptomycin induced deafness in a pattern consistent with matrilineal transmission. Amplified mtDNA, obtained from transformed lymphoblastoid cell lines using previously d escribed primers, showed the A to G point mutation in the 12S rRNA gen e in two of the three families by restriction analysis as well as dire ct sequencing. No other example of this substitution was found among 4 00 control samples from Mongolians with normal hearing. We have thus c onfirmed the clinical relevance of the 1555 A to G mitochondrial mutat ion in the 12S rRNA gene by identifying it in affected subjects with f amilial aminoglycoside ototoxicity in another ethnic group. In countri es where aminoglycosides are widely used, genetic counselling and scre ening of high risk families before the use of these drugs could have a dramatic effect on the incidence of deafness.