TY - JOUR
T1 - TMEM70
T2 - A mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex v biogenesis
AU - Torraco, Alessandra
AU - Verrigni, Daniela
AU - Rizza, Teresa
AU - Meschini, Maria Chiara
AU - Vazquez-Memije, Martha Elisa
AU - Martinelli, Diego
AU - Bianchi, Marzia
AU - Piemonte, Fiorella
AU - Dionisi-Vici, Carlo
AU - Santorelli, Filippo Maria
AU - Bertini, Enrico
AU - Carrozzo, Rosalba
PY - 2012/11
Y1 - 2012/11
N2 - Mammalian 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.
AB - Mammalian 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.
KW - 3-Methylglutaconic aciduria
KW - F1F0-ATP synthase
KW - Hypertrophic cardiomyopathy
KW - Mitochondrial disease
KW - PAH
KW - TMEM70
UR - http://www.scopus.com/inward/record.url?scp=84868300240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868300240&partnerID=8YFLogxK
U2 - 10.1007/s10048-012-0343-8
DO - 10.1007/s10048-012-0343-8
M3 - Article
C2 - 22986587
AN - SCOPUS:84868300240
VL - 13
SP - 375
EP - 386
JO - Neurogenetics
JF - Neurogenetics
SN - 1364-6745
IS - 4
ER -