Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy.

• J M Shoffner

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

• M T Lott

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

• A S Voljavec

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

• S A Soueidan

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

• D A Costigan

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

• D C Wallace

  Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.

抄録

The muscle mitochondria of a patient with Kearns-Sayre/chronic external ophthalmoplegia plus syndrome were found to be completely deficient in respiratory complex I activity and partially deficient in complex IV and V activities. Treatment of the patient with coenzyme Q10 and succinate resulted in clinical improvement of respiratory function, consistent with the respiratory deficiencies. Restriction enzyme analysis of the muscle mtDNA revealed a 4.9-kilobase deletion in 50% of the mtDNA molecules. Polymerase chain reaction analysis demonstrated that the deletion was present in the patient's muscle but not in her lymphocytes or platelets. Furthermore, the deletion was not present in the muscle or platelets of two sisters. Hence, the mutation probably occurred in the patient's somatic cells. Direct sequencing of polymerase chain reaction-amplified DNA revealed a 4977-base-pair deletion removing four genes for subunits of complex I, one gene for complex IV, two genes for complex V, and five genes for tRNAs, which paralleled the respiratory enzymes affected in the disease. A 13-base-pair direct repeat was observed upstream from both breakpoints. Relative to the direction of heavy-strand replication, the first repeat was retained and the second repeat was deleted, suggesting a slip-replication mechanism. Sequence analysis of the human mtDNA revealed many direct repeats of 10 base pairs or greater, indicating that this mechanism could account for other reported deletions. We postulate that the prevalence of direct repeats in the mtDNA is a consequence of the guanine-cytosine bias of the heavy and light strands.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 86 (20), 7952-7956, 1989-10

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1361699996051523968
• NII論文ID: 80004829852
• DOI: 10.1073/pnas.86.20.7952
• ISSN: 10916490
• ISSN: 00278424
• ISSN: http://id.crossref.org/issn/00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.86.20.7952
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