Human Molecular Genetics, Vol 6, 221-228, Copyright © 1997 by Oxford University Press
M Munaro, V Tiranti, D Sandona, E Lamantea, G Uziel, R Bisson and M Zeviani
A generalized defect of complex IV (cytochrome C oxidase, COX) is
frequently found in subacute necrotizing encephalomyelopathy (Leigh's
syndrome), the most common mitochondrial disorder in infancy. We previously
demonstrated the nuclear origin of the COX defect in one case, by fusing
nuclear DNA-less cytoplasts derived from normal fibroblasts with
mitochondrial DNA (mtDNA)-less transformant fibroblasts derived from a
patient with COX-defective [COX(-)] Leigh's syndrome. The resulting cybrid
line showed a specific and serve COX(-) phenotype. Conversely, in the
present study, we demonstrated that a COX(+) phenotype could be restored in
hybrids obtained by fusing COX(-) transformant fibroblasts of seven
additional Leigh's syndrome patients with mtDNA-less, COX(-) tumor-derived
rho degree cells. Both these results are explained by the presence of a
mutation in a nuclear gene. In a second set of experiments, in order to
demonstrate whether COX(-) Leigh's syndrome is due to a defect in the same
gene, or in different genes, we tested several hybrids derived by fusing
our original COX(-) cell line with each of the remaining seven cell lines.
COX activity was evaluated in situ by histochemical techniques and in cell
extracts by a spectrophotometric assay. No COX complementers were found
among the resulting hybrid lines. This result demonstrates that all our
cases were genetically homogeneous, and suggests that a major nuclear
disease locus is associated with several, perhaps most, of the cases of
infantile COX(-) Leigh's syndrome. This information should make it easier
to identify the gene responsible.
ARTICLES
A single cell complementation class is common to several cases of cytochrome c oxidase-defective Leigh's syndrome
Division of Biochemistry and Genetics, National Neurological Institute, C. Besta, Milan, Italy.
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