Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation

The pathogenetic mechanism of the human mito- chondrial 128 rRNA gene mutat ion at position 1555, associated with non-syndromic deafness and aminoglyco side-induced deafness, has been investi gated in 33 transformants obtained by transferring mitochondria from lymphoblastoid cell lines into human mito chondrial DNA (mtDNA)-less (p degrees 206) cells. In this nearly constant n uclear background, 15 transformants derived from five symptomatic individua ls from a large Arab-israeli family, carrying this mutation in homoplasmic form, exhibited significant decreases compared with nine control transforma nts in the rate of growth in a medium containing galactose instead of gluco se, as well as in the rates of mitochondrial protein synthesis and of subst rate- dependent respiration. Most significantly, these decreases were very similar to those observed in nine transformants derived from three asymptom atic members of the family. This result in transmitochondrial cybrids is in contrast to the differences in the same parameters previously demonstrated between the original lymphoblastoid cell lines derived from symptomatic an d asymptomatic members of the glycoside-induced deafness and non-syndromic deafness Arab-Israeli family. In addition, the intragroup variability in bi ochemical dysfunction among the lymphoblastoid cell lines from different sy mptomatic or asymptomatic or control individuals was significantly reduced in the derived mitochondrial transformants carrying the same nuclear backgr ound. These observations provide strong genetic and biochemical evidence in support of the idea that the nuclear background plays a determinant role i n the phenotypic manifestation of the non-syndromic deafness associated wit h the A1555G mutation.