ORIGINAL ARTICLES

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy

A I Jonckheere¹, M Hogeveen¹, L G J Nijtmans¹, M A M van den Brand¹, A J M Janssen¹, J H S Diepstra¹, F C A van den Brandt¹, L P van den Heuvel¹, F A Hol², T G J Hofste², L Kapusta¹, U Dillmann³, M G Shamdeen³, J A M Smeitink¹, R J T Rodenburg¹

¹ Department of Pediatrics at the Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
² Human Genetics at the Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
³ Departments of Neurology and Pediatric and Juvenile Medicine, Saarland University, Homburg, Saar, Germany

Professor J A M Smeitink, Nijmegen Centre for Mitochondrial Disorders, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands; j.smeitink{at}cukz.umcn.nl

Purpose: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.

Methods: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK^– rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly.

Results: A homoplasmic nonsense mutation m.8529GA (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient’s fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient’s fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F₁-ATPase in the patient’s muscle tissue and in the cybrid clones.

Conclusion: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

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