title: A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
abstract: Defects in the respiratory chain or mitochondrial ATP synthase (complex V) result in mitochondrial dysfunction that is an important cause of inherited neurological disease. Two of the subunits of complex V are encoded by MT-ATP6 and MT-ATP8 in the mitochondrial genome. Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease. We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism. As the phenotype was suggestive of mitochondrial disease, mitochondrial DNA was sequenced and a novel heteroplasmic mutation m.8561C>G in the overlapping region of the MT-ATP6 and MT-ATP8 was found. The mutation changed amino acids in both subunits. Mutation heteroplasmy correlated with the disease phenotype in five family members. An additional assembly intermediate of complex V and increased amount of subcomplex F1were observed in myoblasts of the two patients, but the total amount of complex V was unaffected. Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production. We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.
authors: Research Unit of Clinical Neuroscience, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Department of Neurology, Oulu University Hospital, P.O. Box 20, 90029, Oulu, Finland.
authors: Laura
authors: L
authors: Kytövuori
authors: Research Unit of Clinical Neuroscience, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Department of Neurology, Oulu University Hospital, P.O. Box 20, 90029, Oulu, Finland.
authors: Joonas
authors: J
authors: Lipponen
authors: Research Unit of Clinical Neuroscience, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.|Department of Neurology, Oulu University Hospital, P.O. Box 20, 90029, Oulu, Finland.
authors: Harri
authors: H
authors: Rusanen
authors: PEDEGO Research Unit, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland.
authors: Tuomas
authors: T
authors: Komulainen
authors: Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20520, Turku, Finland.
authors: Mika H
authors: MH
authors: Martikainen
authors: Research Unit of Clinical Neuroscience, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland. kari.majamaa@oulu.fi.|Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. kari.majamaa@oulu.fi.|Department of Neurology, Oulu University Hospital, P.O. Box 20, 90029, Oulu, Finland. kari.majamaa@oulu.fi.
authors: Kari
authors: K
authors: Majamaa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000150:complications / Q000235:genetics*; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000235:genetics*
chemical_list: C501005:MT-ATP6 protein, human; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: Gait disorders; Hypergonadotropic hypogonadism; Mitochondrial disorders; Neuromuscular disease