TMEM70

Transmembrane protein 70 is a protein that in humans is encoded by the TMEM70 gene. It is a transmembrane protein located in the mitochondrial inner membrane involved in the assembly of the F1 and Fo structural subunits of ATP synthase.[5] Mutations in this gene have been associated with neonatal mitochondrial encephalo-cardiomyopathy due to ATP synthase (Complex V) deficiency, causing a wide variety of symptoms including 3-methylglutaconic aciduria, lactic acidosis, mitochondrial myopathy, and cardiomyopathy.[6][7]

TMEM70
Identifiers
AliasesTMEM70, MC5DN2, transmembrane protein 70
External IDsOMIM: 612418 MGI: 1915068 HomoloGene: 9890 GeneCards: TMEM70
Gene location (Human)
Chr.Chromosome 8 (human)[1]
Band8q21.11Start73,972,437 bp[1]
End73,982,783 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

54968

70397

Ensembl

ENSG00000175606

ENSMUSG00000025940

UniProt

Q9BUB7

Q921N7

RefSeq (mRNA)

NM_001040613
NM_017866

NM_026392
NM_027415

RefSeq (protein)

NP_001035703
NP_060336

NP_080668
NP_081691

Location (UCSC)Chr 8: 73.97 – 73.98 MbChr 1: 16.67 – 16.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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 conserved domain 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]

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.[13] 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.[14]

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]

Interactions

The encoded protein has protein-protein interactions with RAB2A, PHC2, NDUFAF8, NDUFS5, COX6B1, ECSIT, NDUFAF4, and COA3.[16]

References

  1. GRCh38: Ensembl release 89: ENSG00000175606 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000025940 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: Transmembrane protein 70". Retrieved 2018-08-14. This article incorporates text from this source, which is in the public domain.
  6. Online Mendelian Inheritance in Man (OMIM): TMEM70 - 612418
  7. Cameron JM, Levandovskiy V, Mackay N, Ackerley C, Chitayat D, Raiman J, et al. (January 2011). "Complex V TMEM70 deficiency results in mitochondrial nucleoid disorganization". Mitochondrion. 11 (1): 191–9. doi:10.1016/j.mito.2010.09.008. PMID 20920610.
  8. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  9. "TMEM70 - Transmembrane protein 70, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  10. "TMEM70 - Transmembrane protein 70, mitochondrial precursor - Homo sapiens (Human) - TMEM70 gene & protein". www.uniprot.org. Retrieved 2018-08-15. This article incorporates text available under the CC BY 4.0 license.
  11. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  12. 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. PMID 18953340. S2CID 34536246.
  13. 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. PMID 24485043.
  14. Honzík T, Tesarová M, Mayr JA, Hansíková H, Jesina P, Bodamer O, et al. (April 2010). "Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation". Archives of Disease in Childhood. 95 (4): 296–301. doi:10.1136/adc.2009.168096. hdl:1854/LU-987464. PMID 20335238. S2CID 2946094.
  15. 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. PMID 21147908. S2CID 8699153.
  16. IntAct. "TMEM70 interactions". www.ebi.ac.uk. Retrieved 2018-08-16.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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