BIOCHEMICAL-CHARACTERIZATION OF A PEDIGREE WITH MITOCHONDRIALLY INHERITED DEAFNESS

A large kindred with a predicted 2-locus inheritance of sensorineural deafness, caused by the combination of a mitochondrial and an autosomal recessive mutation, was examined at the biochemical level. Because of the mitochondrial inheritance of this disease, we looked for defects in the oxidative phosphorylation Complexes I, III, IV, and V, the 4 enzymes that include all of the 13 mitochondrially encoded polypeptides. Biosynthetic labelling of lymphoblastoid cells from deaf patients, unaffected siblings, and an unrelated control showed no difference in size, abundance, rate of synthesis, or chloramphenicol-sensitivity of the mitochondrially encoded subunits. Since overall mitochondrial protein synthesis appears normal, these results suggest that the mitochondrial mutation is unlikely to be in a tRNA or rRNA gene. No change in enzymatic levels was seen in lymphoblastoid mitochondria of the deaf patients, compared to unaffected sibs and controls, for Complexes I and IV. Both affected and unaffected family members showed an increase in Complex III activity compared to controls, which may reflect the mitochondrial DNA shared by maternal relatives, or be due to other genetic differences. Complex V activity was increased in deaf individuals compared to their unaffected sibs. Since the family members share the presumptive mitochondrial mutation, differences between deaf and unaffected individuals likely reflect the nuclear background and suggest that the autosomal recessive mutation may be related to the increase in Complex V activity. These biochemical studies provide a guide for sequence analysis of the patients' mitochondrial DNA and for linkage studies in this kindred.