Human Molecular Genetics, Vol 5, 963-971, Copyright © 1996 by Oxford University Press
MX Guan, N Fischel-Ghodsian and G Attardi
The phenotypic effects of the human mitochondrial 12S rRNA gene mutation at
position 1555 associated with maternally inherited non- syndromic deafness
and sensitivity to aminoglycoside-induced deafness have been analyzed in 25
lymphoblastoid cell lines derived from members of a large family carrying
this mutation in homoplasmic form and from control individuals. A clear
decrease in the rates of growth in galactose medium, mitochondrial protein
synthesis, total oxygen consumption, and complex I-, complex III- and
complex IV-dependent respiration was observed in two groups of nine and 10
mutant cell lines derived, respectively, from symptomatic and asymptomatic
members of the family, as compared with six control cell lines. The
severity of mitochondrial dysfunction in the mutant cell lines was
correlated with the presence or absence of hearing loss in the donor
individuals. These observations strongly suggest a role of a nuclear
factor(s) in the phenotypic manifestation of the mutation. The approach
used here provides a paradigm for the analysis of the nuclear background
involvement in other mtDNA-linked disorders, including the putative ones
associated with neurodegenerative diseases. Exposure of the cell lines
derived from several symptomatic or asymptomatic individuals from the same
family to high concentrations of neomycin or paromomycin decreased to a
significant, nearly identical extent their rate of growth in
glucose-containing medium, as contrasted with the unchanged growth rate of
control cell lines or of mtDNA-less cells. These results support the
hypothesis that the main target of the antibiotics is the mitochondrial 12S
rRNA carrying the 1555 mutation, without any apparent role of the nuclear
background.
ARTICLES
Biochemical evidence for nuclear gene involvement in phenotype of non- syndromic deafness associated with mitochondrial 12S rRNA mutation
Division of Biology, California Institute of Technology, Pasadena 91125, USA.
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