Exercise Intolerance Due to Mutations in the CytochromebGene of Mitochondrial DNA

作者：Antoni L. Andreu, Michael G. Hanna, Heinz Reichmann, Claudio Bruno, Audrey S. Penn, Kurenai Tanji, Francesco Pallotti, So Iwata, Eduardo Bonilla, Bolesław Lach, JOHN A. MORGAN-HUGHES, Sara Shanske, Carolyn M. Sue, Teeratorn Pulkes, Asra Tus Saleha Siddiqui, John Bates Clark, John M. Land, Momi Iwata, Jochen Schaefer, Salvatore DiMauro · 发表于：New England Journal of Medicine · 年份：1999 · DOI：10.1056/nejm199909303411404 · 被引用次数：432 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Nuclear Structure and Function

BACKGROUND: The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. METHODS: We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. RESULTS: We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (from nucleotide 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-la...