MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases

• Published in: Human mutation Vol. 40; no. 5; pp. 499 - 515
• Main Authors: Ganetzky, Rebecca D., Stendel, Claudia, McCormick, Elizabeth M., Zolkipli‐Cunningham, Zarazuela, Goldstein, Amy C., Klopstock, Thomas, Falk, Marni J.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2019
• Subjects: Adenosine triphosphate; Alleles; Animals; Biomarkers; Cohort Studies; Diagnostic Tests, Routine; Disease; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genotype; genotype–phenotype correlation; Heteroplasmy; Humans; Inheritance Patterns; Leigh syndrome; Membrane potential; mitochondria; Mitochondrial Diseases - diagnosis; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial DNA; Mitochondrial Proton-Translocating ATPases - genetics; Mitochondrial Proton-Translocating ATPases - metabolism; Mutation; neurogenic ataxia and retinitis pigmentosa; Pathogenicity; Phenotype; heteroplasmy; Leigh syndrome; neurogenic ataxia and retinitis pigmentosa; mitochondria; genotype-phenotype correlation
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.23723

Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G pathogenic variant in the CV subunit gene MT‐ATP6 was among the first described human mitochondrial DNA diseases. Due to a lack of clinically available functional assays, validating the definitive pathogenicity of additional MT‐ATP6 variants remains challenging. We reviewed all reportedMT‐ATP6 disease cases ( n = 218) to date, to assess for MT‐ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT‐ATP6 variants of uncertain significance. Despite extensive overlap in the heteroplasmy levels of MT‐ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load (p = 2.2 x 10‐16). Pathogenic MT‐ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT‐ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT‐ATP6. Mitochondrial disease caused by the m.8993T>G pathogenic variant in CV subunit gene, MT‐ATP6, was among the first described human mitochondrial DNA (mtDNA) diseases. Due to a lack of clinically available functional assays, validating the definitive pathogenicity of additional MT‐ATP6 variants remains challenging. We reviewed all reported MT‐ATP6 disease cases (n = 218) as well as 14 novel cases, to assess for MT‐ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings.