The TMEM70 gene has 4 exons and is located on the q arm of chromosome 8 in position 21.11 and spans 6,642 base pairs.[5] The gene produces a 29 kDa protein composed of 260 amino acids.[8][9] The encoded protein is a multi-pass transmembrane protein localized to the mitochondrial inner membrane.[10][11] It contains two putative transmembrane regions and the conserveddomain DUF1301.[12][6]
Function
The encoded protein is involved in the assembly of the F1 and Fo structural subunits of ATP synthase.[5]
Clinical significance
Mutations in the TMEM70 gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to nuclear type 2 Complex V (ATP synthase) deficiency.[5] There are a wide variety of possible symptoms depending on the mutation, including 3-methylglutaconic aciduria, dysmorphic features, psychomotor retardation, hypotonia, growth retardation, mitochondrial myopathy and cardiomyopathy, hepatomegaly, hypoplastic kidneys, and elevated lactate levels in urine, plasma, and cerebrospinal fluid.[11][7]
Another mutation (c.366A>T) in the second exon of this gene caused an amino acid substitution (Y112X), resulting in Nuclear Type 2 Mitochondrial Complex V deficiency symptomized by lactic acidosis, psychomotor retardation, facial dysmorphism, hypertrophic cardiomyopathy, and hypospadia.[15][6]
A study of mitochondrial morphology in patients with mutations in this gene revealed disorganization of the mitochondrial nucleoid. Mitochondria were abnormal, with whorled cristae and disrupted nucleoid clusters of mtDNA. The nucleoids and mitochondrial respiratory chain complexes were confined to the outer rings of the whorls.[7]
^Cízková A, Stránecký V, Mayr JA, Tesarová M, Havlícková V, Paul J, et al. (November 2008). "TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy". Nature Genetics. 40 (11): 1288–90. doi:10.1038/ng.246. PMID18953340. S2CID34536246.
^Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafé L, et al. (March 2014). "Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients". Molecular Genetics and Metabolism. 111 (3): 353–359. doi:10.1016/j.ymgme.2014.01.001. PMID24485043.
^Spiegel R, Khayat M, Shalev SA, Horovitz Y, Mandel H, Hershkovitz E, et al. (March 2011). "TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome". Journal of Medical Genetics. 48 (3): 177–82. doi:10.1136/jmg.2010.084608. PMID21147908. S2CID8699153.
Jonckheere AI, Huigsloot M, Lammens M, Jansen J, van den Heuvel LP, Spiekerkoetter U, von Kleist-Retzow JC, Forkink M, Koopman WJ, Szklarczyk R, Huynen MA, Fransen JA, Smeitink JA, Rodenburg RJ (November 2011). "Restoration of complex V deficiency caused by a novel deletion in the human TMEM70 gene normalizes mitochondrial morphology". Mitochondrion. 11 (6): 954–63. doi:10.1016/j.mito.2011.08.012. PMID21945727.
