Alessandra Torraco, Daniela Verrigni, Teresa Rizza, Maria Chiara Meschini, Martha Elisa Vazquez-Memije, Diego Martinelli, Marzia Bianchi, Fiorella Piemonte, Carlo Dionisi-Vici, Filippo Maria Santorelli, Enrico Bertini, Rosalba Carrozzo
Neurogenetics 2012 NovMammalian complex V (F1F0-ATP synthase or ATPase) uses the proton gradient to generate ATP during oxidative phosphorylation and requires several helper proteins, including TMEM70, to form the holoenzyme in a stepwise process in which nuclear DNA is combined with mitochondrial DNA-encoded subunits. We report the clinical and molecular findings in three patients presenting lactic acidosis, 3-methylglutaconic aciduria, and hypertrophic cardiomyopathy. All three showed an isolated defect of fully assembled ATP synthase in association with a "common" (c.317-2A > G) and a new (c.628A > C/p.T210P) variant in TMEM70. Interestingly, one of the patients also showed nitric oxide-responsive pulmonary arterial hypertension, a finding never before associated with TMEM70 deficiency. In addition to widening the clinical and mutational spectrum of defective ATP synthase, our study also suggests that mutant TMEM70 associates in high molecular weight complexes (470-550 kDa) when expressed in Hela cells and exerts a direct action in ATP synthase biogenesis and assembly, mediating the incorporation of F1 moieties.
Alessandra Torraco, Daniela Verrigni, Teresa Rizza, Maria Chiara Meschini, Martha Elisa Vazquez-Memije, Diego Martinelli, Marzia Bianchi, Fiorella Piemonte, Carlo Dionisi-Vici, Filippo Maria Santorelli, Enrico Bertini, Rosalba Carrozzo. TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis. Neurogenetics. 2012 Nov;13(4):375-86
PMID: 22986587
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