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Cytochrome c oxidase deficiency in Leigh's syndrome

Genetic evidence for a nuclear DNA-encoded mutation

Department of Pathology, College of Physicians and Surgeons, Columbia university, New York, NY (Dr. Miranda)
Department of and Neurology, College of Physicians and Surgeons, Columbia university, New York, NY (Dr. DiMauro)
University of Texas Southwestern Medical Center at Dallas Dallas, TX. (Drs. Shay and Ishii).

Although an apparently generalized defect of cytochrome c oxidase (COX) occurs in many patients with subacute necrotizing encephalomyelopathy (Leigh's syndrome), the mode of inheritance in this disorder is not known. We transformed COX-deficient fibroblasts from a child with Leigh's syndrome with simian virus 40 to obtain cells with an infinite life span. These cells were still COX-deficient, grew normally in HAT medium, and were ouabain-sensitive. We fused these cells with a HAT-sensitive, ouabain-resistant variant of HeLa cells (HeLacot) and isolated surviving hybrid clones in ouabain-containing HAT medium. Prolonged cultivation of the hybrids was accompanied by preferential loss of HeLacot mitochondrial DNA (mtDNA), as determined by mtDNA restriction patterns of parental and hybrid cell DNA with the restriction endonuclease HaeII. COX activity was normal or higher than normal in hybrids, including the progeny of cell clones that had lost almost all the HeLacot mtDNA. These data demonstrate that COX deficiency in this Leigh's syndrome patient's cells was corrected by a nuclear DNA-encoded factor from the HeLacot parent and ruled out an mtDNA mutation as the basis for COX deficiency. This system can be used to determine whether different generalized mitochondrial disorders are due to mutations of nuclear or mtDNA.

Address correspondence and reprint requests to Dr. Miranda, Columbia University, College of Physicians and Surgeons, Department of Pathology, 630 West 168th Street. New York, NY 10032.

Supported by center Southwestern Medical Center Grants from the National Institute of Neurologocal and Communicative Disorders and Stroke NS 11766 and the Muscular Dystrophy Association (A.F.M. and S.D.M.), The Council for Tobacco Research, USA, and The American Cancer Society, CD 347 (J.W.S.).

Presented in part at the fortieth annual meeting of the American Academy of Neurology. Cincinnati, OH, April 1988.

Received July 29, 1988. Accepted for publication in final form November 2, 1988.

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