HGNC Approved Gene Symbol: TMEM70
Cytogenetic location: 8q21.11 Genomic coordinates (GRCh38) : 8:73,976,195-73,982,783 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.11 | Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2 | 614052 | Autosomal recessive | 3 |
TMEM70 is a mitochondrial protein required for the assembly of complex I (see 602694) and complex V (see 102910) in the oxidative phosphorylation system (OXPHOS) (Sanchez-Caballero et al., 2020).
Using a computational approach to identify genes encoding putative mitochondrial proteins, Calvo et al. (2006) identified full-length TMEM70 and subsequently cloned the corresponding cDNA. Fluorescence-tagged TMEM70 colocalized with a mitochondrial marker in transfected HeLa cells.
Cizkova et al. (2008) identified TMEM70 within a region of chromosome 8 associated with a form of mitochondrial ATP synthase deficiency (614052). The deduced protein contains a conserved DUF1301 domain and 2 putative transmembrane regions. RT-PCR detected TMEM70 in all tissues examined, which included liver, muscle, kidney, and pancreas, as well as in fibroblasts. Phylogenetic analysis revealed TMEM70 orthologs in multicellular eukaryotes and plants, but not in yeast and fungi.
By phylogenetic analysis, Sanchez-Caballero et al. (2020) identified human TMEM223 (620434) and TMEM186 (620433) as paralogs of TMEM70, even though TMEM70 shares only 9% and 14% amino acid identity with TMEM223 and TMEM186, respectively. Fractionation and immunofluorescence assays showed that TMEM70, TMEM223, and TMEM186 were mitochondrial proteins. In silico analysis suggested that TMEM70, TMEM223, and TMEM186 share a similar asymmetric hairpin topology, with a short N-terminal sequence located in the mitochondrial matrix followed by an in/out and an out/in transmembrane helix and a longer C-terminal sequence. All 3 proteins are phylogenetically widespread and are present in the last eukaryotic common ancestor. As a mitochondrial protein family, all 3 coevolved with the oxidative phosphorylation system (OXPHOS) and only occur in species with OXPHOS.
By genomic sequence analysis, Cizkova et al. (2008) mapped the TMEM10 gene to chromosome 8. Hartz (2008) mapped the TMEM70 gene to chromosome 8q21.11 based on an alignment of the TMEM70 sequence (GenBank AK000540) with the genomic sequence (build 36.1).
Following transfection of wildtype TMEM70 into skin fibroblasts obtained from individuals with isolated mitochondrial ATP synthase deficiency due to mutations in the TMEM70 gene, Cizkova et al. (2008) observed increased amounts of F1 and Fo structural subunits of ATP synthase and production of normal concentrations of full size, assembled ATP synthase complex. Consequently, TMEM70 restored oligomycin-sensitive ATP hydrolysis, ADP-stimulated respiration, mitochondrial ATP synthesis, and ADP-induced decrease of mitochondrial membrane potential.
Using biotin-labeled TMEM70, Sanchez-Caballero et al. (2020) showed that TMEM70 was associated with OXPHOS complex I, complex V, and the small subunit of the ribosome in HEK293 cells. TMEM70 knockout analysis confirmed interaction of TMEM70 with complex I and complex V, as loss of TMEM70 resulted in decreased abundance of the subunits of complex I and complex V and decreased activities of complex I and complex V. Further analysis confirmed that assembly of complexes I and V was impaired in the absence of TMEM70, as loss of TMEM70 resulted in accumulation of an assembly intermediate followed by a reduction of the next assembly intermediate in the pathway. Despite TMEM70 interaction with the small subunit of the ribosome, the assembly process of ribosomes and translation efficiency in mitochondria were not affected by TMEM70 knockout, suggesting that TMEM70 did not play a significant role in assembly or functioning of the ribosome.
Carroll et al. (2021) identified TMEM70 and TMEM242 (620721) as assembly factors associated with subunit c (see 602736) of ATP synthase in HEK293 cells. Knockout of TMEM242 or TMEM70 in HAP1 cells altered but did not eliminate assembly of ATP synthase and, to a lesser degree, respiratory enzyme complexes I, III (see 516020), and IV (see 516030). Deletion of both TMEM70 and TMEM242 prevented assembly of ATP synthase and enhanced the effects on complex I resulting from deletion of TMEM242 or TMEM70. Removal of TMEM242, but not of TMEM70, also affected introduction of subunits ATP6 (MTATP6; 516060), ATP8 (MTATP8; 516070), j (ATP5MJ), and k (ATP5MK) into ATP synthase. Further analysis revealed that TMEM70 and TMEM242 also interacted with the mitochondrial complex I assembly (MCIA) complex, which supports assembly of the membrane arm of complex I.
In affected individuals from 6 Romani families with neonatal mitochondrial encephalocardiomyopathy associated with complex V (ATP synthase) deficiency (MC5DN2; 614052), Cizkova et al. (2008) identified a homozygous mutation in the TMEM70 gene (612418.0001). The same homozygous mutation was identified in 23 additional patients. Cooccurrence of cases with severe and milder phenotypes with the same mutation was thought to represent varying quality and functionality of individual nonsense-mediated RNA decay systems.
In 6 patients from 4 unrelated consanguineous Arab-Muslim families with MC5DN2, Spiegel et al. (2011) identified 4 different homozygous mutations in the TMEM70 gene (see, e.g., 612418.0003-612418.0005).
In 2 Bedouin sibs, born to consanguineous parents, with MC5DN2, Staretz-Chacham et al. (2019) identified a homozygous frameshift mutation in the TMEM70 gene (612418.0006). The mutation was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. Family segregation studies were not performed. The variant was not found in the dbSNP (build 150) or ExAC databases but was present at a low frequency (0.0009248%) in the gnomAD database. It was not found in 153 ethnically matched controls.
In affected members of 6 families with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052), Cizkova et al. (2008) identified a homozygous A-to-G transition in intron 2 of the TMEM70 gene (c.317-2A-G), resulting in aberrant splicing and loss of the mRNA transcript. The same homozygous mutation was identified in 23 additional patients. One patient was compound heterozygous for this mutation and a 2-bp insertion (118_119insGT; 612418.0002).
Catteruccia et al. (2014) identified a homozygous c.317-2A-G mutation in 6 of 9 patients with MC5DN2.
For discussion of the 2-bp insertion in the TMEM70 gene (118_119insGT) that was found in compound heterozygous state in a patient with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052) by Cizkova et al. (2008), see 612418.0001.
In an 11-month-old boy, born of consanguineous Arab Muslim parents, with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052), Spiegel et al. (2011) identified a homozygous 366A-T transversion in exon 2 of the TMEM70 gene, resulting in a tyr112-to-ter (Y112X) substitution. The patient had hypertrophic cardiomyopathy, lactic acidosis, mild psychomotor retardation, hypospadias, and facial dysmorphism. Skeletal muscle complex V activity was 16% of controls.
In a female infant, born of consanguineous Arab Muslim parents, with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052), Spiegel et al. (2011) identified a homozygous 238C-T transition in exon 2 of the TMEM70 gene, resulting in an arg80-to-ter (R80X) substitution. At birth, the patient showed respiratory insufficiency and hypotonia, and soon developed severe lactic acidosis and impaired liver function, followed by death from multiorgan failure at age 7 days. Skeletal muscle complex V activity was 4% of controls.
In 2 sibs, born of consanguineous Arab Muslim parents, with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052), Spiegel et al. (2011) identified a homozygous 2-bp deletion (578delCA) in exon 3 of the TMEM70 gene, resulting in a truncated 197-residue protein. One brother was alive at age 26 years, and the other died at age 3. Both had hypotonia, hypertrophic cardiomyopathy, recurrent encephalopathic episodes, lactic acidosis, 3-methylglutaconic aciduria, and severe psychomotor retardation. Other features included infantile cataract and delayed gastric emptying. Skeletal muscle complex V activity was undetectable in the surviving patient.
In 2 Bedouin sibs, born to consanguineous parents, with mitochondrial complex V deficiency nuclear type 2 (MC5DN2; 614052), Staretz-Chacham et al. (2019) identified a homozygous 1-bp duplication (c.105dupT, NM_017866.5) in exon 1 of the TMEM70 gene, resulting in a frameshift and a premature termination codon (Val36CysfsTer52). The mutation was predicted to result in loss of function of the protein. The mutation was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. Family segregation studies were not performed. The variant was not found in the dbSNP (build 150) or ExAC databases but was present at a low frequency (0.0009248%) in the gnomAD database. It was not found in 153 ethnically matched controls.
Calvo, S., Jain, M., Xie, X., Sheth, S. A., Chang, B., Goldberger, O. A., Spinazzola, A., Zeviani, M., Carr, S. A., Mootha, V. K. Systematic identification of human mitochondrial disease genes through integrative genomics. Nature Genet. 38: 576-582, 2006. [PubMed: 16582907] [Full Text: https://doi.org/10.1038/ng1776]
Carroll, J., He, J., Ding, S., Fearnley, I. M., Walker, J. E. TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I. Proc. Nat. Acad. Sci. 118: e2100558118, 2021. [PubMed: 33753518] [Full Text: https://doi.org/10.1073/pnas.2100558118]
Catteruccia, M., Verrigni, D., Martinelli, D., Torraco, A., Agovino, T., Bonafe, L., D'Amico, A., Donati, M. A., Adorisio, R., Santorelli, F. M., Carrozzo, R., Bertini, E., Dionisi-Vici, C. Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. Molec. Genet. Metab. 111: 353-359, 2014. [PubMed: 24485043] [Full Text: https://doi.org/10.1016/j.ymgme.2014.01.001]
Cizkova, A., Stranecky, V., Mayr, J. A., Tesarova, M., Havlickova, V., Paul, J., Ivanek, R., Kuss, A. W., Hansikova, H., Kaplanova, V., Vrbacky, M., Hartmannova, H., and 9 others. TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nature Genet. 40: 1288-1290, 2008. [PubMed: 18953340] [Full Text: https://doi.org/10.1038/ng.246]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/18/2008.
Sanchez-Caballero, L., Elurbe, D. M., Baertling, F., Guerrero-Castillo, S., van den Brand, M., van Strien, J., van Dam, T. J. P., Rodenburg, R., Brandt, U., Huynen, M. A., Nijtmans, L. G. J. TMEM70 functions in the assembly of complexes I and V. Biochim. Biophys. Acta Bioenerg. 1861: 148202, 2020. [PubMed: 32275929] [Full Text: https://doi.org/10.1016/j.bbabio.2020.148202]
Spiegel, R., Khayat, M., Shalev, S. A., Horovitz, Y., Mandel, H., Hershkovitz, E., Barghuti, F., Shaag, A., Saada, A., Korman, S. H., Elpeleg, O., Yatsiv, I. TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome. J. Med. Genet. 48: 177-182, 2011. [PubMed: 21147908] [Full Text: https://doi.org/10.1136/jmg.2010.084608]
Staretz-Chacham, O., Wormser, O., Manor, E., Birk, O. S., Ferreira, C. R. TMEM70 deficiency: novel mutation and hypercitrullinemia during metabolic decompensation. Am. J. Med. Genet. 179A: 1293-1298, 2019. [PubMed: 30950220] [Full Text: https://doi.org/10.1002/ajmg.a.61138]