TMEM70

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. The gene produces a 29 kDa protein composed of 260 amino acids.{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | display-authors = 6 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}{{cite web|url=https://amino.heartproteome.org/web/protein/Q8N5M1|title=TMEM70 - Transmembrane protein 70, mitochondrial|work=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} The encoded protein is a multi-pass transmembrane protein localized to the mitochondrial inner membrane.{{Cite web|url=https://www.uniprot.org/uniprot/Q9BUB7|title=TMEM70 - Transmembrane protein 70, mitochondrial precursor - Homo sapiens (Human) - TMEM70 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-15}}{{CC-notice|cc=by4}}{{cite journal | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }} It contains two putative transmembrane regions and the conserved domain DUF1301.{{cite journal | vauthors = Cízková A, Stránecký V, Mayr JA, Tesarová M, Havlícková V, Paul J, Ivánek R, Kuss AW, Hansíková H, Kaplanová V, Vrbacký M, Hartmannová H, Nosková L, Honzík T, Drahota Z, Magner M, Hejzlarová K, Sperl W, Zeman J, Houstek J, Kmoch S | display-authors = 6 | title = TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy | journal = Nature Genetics | volume = 40 | issue = 11 | pages = 1288–90 | date = November 2008 | pmid = 18953340 | doi = 10.1038/ng.246 | s2cid = 34536246 }}

The encoded protein is involved in the assembly of the F1 and Fo structural subunits of ATP synthase.

Mutations in the TMEM70 gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to nuclear type 2 Complex V (ATP synthase) deficiency. 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.

Most notably, a c.317-2A→G mutation in the splice site of intron 2 of this gene caused aberrant splicing and the loss of the TMEM70 transcript.{{cite journal | vauthors = Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafé L, D'Amico A, Donati MA, Adorisio R, Santorelli FM, Carrozzo R, Bertini E, Dionisi-Vici C | display-authors = 6 | title = Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients | journal = Molecular Genetics and Metabolism | volume = 111 | issue = 3 | pages = 353–359 | date = March 2014 | pmid = 24485043 | doi = 10.1016/j.ymgme.2014.01.001 }} This resulted in ATP synthase deficiency symptomized by apneoic spells, hypertrophic cardiomyopathy, profound lactic acidosis, hyperammonaemia, psychomotor retardation, 3-methylglutaconic aciduria, failure to thrive, and severe muscular hypotonia. Also noted in some patients were hypospadias, intrauterine growth retardation, microcephaly and cryptorchidism, but most patients did not survive the neonatal period.{{cite journal | vauthors = Honzík T, Tesarová M, Mayr JA, Hansíková H, Jesina P, Bodamer O, Koch J, Magner M, Freisinger P, Huemer M, Kostková O, van Coster R, Kmoch S, Houstêk J, Sperl W, Zeman J | display-authors = 6 | title = Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation | journal = Archives of Disease in Childhood | volume = 95 | issue = 4 | pages = 296–301 | date = April 2010 | pmid = 20335238 | doi = 10.1136/adc.2009.168096 | url = https://biblio.ugent.be/publication/987464/file/999385 | hdl = 1854/LU-987464 | s2cid = 2946094 | hdl-access = free }}

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.{{cite journal | vauthors = Spiegel R, Khayat M, Shalev SA, Horovitz Y, Mandel H, Hershkovitz E, Barghuti F, Shaag A, Saada A, Korman SH, Elpeleg O, Yatsiv I | display-authors = 6 | title = TMEM70 mutations are a common cause of nuclear encoded ATP synthase assembly defect: further delineation of a new syndrome | journal = Journal of Medical Genetics | volume = 48 | issue = 3 | pages = 177–82 | date = March 2011 | pmid = 21147908 | doi = 10.1136/jmg.2010.084608 | s2cid = 8699153 }}

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.

The encoded protein has protein-protein interactions with RAB2A, PHC2, NDUFAF8, NDUFS5, COX6B1, ECSIT, NDUFAF4, and COA3.{{Cite web|url=https://www.ebi.ac.uk/intact/interactors/id:Q9BUB7*#|title=TMEM70 interactions|last=IntAct|website=www.ebi.ac.uk|language=en|access-date=2018-08-16}}

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