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词条 MPV17
释义

  1. Function

  2. Structure

      Gene    Protein  

  3. Clinical significance

  4. Interactions

  5. References

  6. Further reading

{{Infobox_gene}}Protein MPV17 is a protein that in humans is encoded by the MPV17 gene.[1][2][3] It is a mitochondrial inner membrane protein, which has a so far largely unknown role in mtDNA maintenance. Protein MPV17 is expressed in human pancreas, kidney, muscle, liver, lung, placenta, brain and heart.[4] Human MPV17 is the orthologue of the mouse kidney disease gene, Mpv17. Loss of function has been shown to cause hepatocerebral mtDNA depletion syndromes (MDS) with oxidative phosphorylation failure and mtDNA depletion both in affected individuals and in Mpv17−/− mice.[2][5]

Function

This protein was first thought to be a peroxisomal protein, but in 2006, Spinazzola demonstrated that it is a mitochondrial inner membrane protein that is implicated in the formation of reactive oxygen species (ROS).

Restoration of Mpv17 expression in a Mpv17-/- mice restore mtDNA copy number, suggesting MPV17 is involved in mtDNA copy number, and in mtDNA maintenance.[6]

MPV17 seems to be also involved in apoptosis in podocytes, and involved in ROS.[7]

Structure

Gene

The human MPV17 gene is located on chromosome 2 at p21-23, comprising eight exons encoding 176 amino acids.[3]

Protein

MPV17 belongs to a family of integral membrane proteins consisting of four members (PXMP2, MPV17, MP-L, and FKSG24 (MPV17L2)) in mammals and two members (Sym1 and Yor292) in yeast. The amino acid sequence of MPV17 (176 amino acids) contains four cysteine residues and three putative phosphorylation sites implies that this protein may act as a redox- and ATP-sensitive channel.[8]

Clinical significance

Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS), a mutation in this protein leads to an mtDNA (mitochondrial DNA) copy number decrease.[3] By 2013, MDS caused by MPV17 mutations had been reported in 32 patients with the clinical manifestations including early progressive liver failure, neurological abnormalities, hypoglycaemia and raised blood lactate.[4] In addition, MPV17 mutations have also been associated with autosomal recessive adult-onset neuropathy and leukoencephalopathy with multiple mtDNA deletions in skeletal muscle.[9] Thus, MPV17 mutations can lead to recessive MDS or recessive multiple mtDNA deletion disorders.

Interactions

MPV17 has been shown to interact with Prkdc protein during Adriamycin-induced nephropathy in mice.[10]

References

1. ^{{cite journal | vauthors = Karasawa M, Zwacka RM, Reuter A, Fink T, Hsieh CL, Lichter P, Francke U, Weiher H | title = The human homolog of the glomerulosclerosis gene Mpv17: structure and genomic organization | journal = Human Molecular Genetics | volume = 2 | issue = 11 | pages = 1829–34 | date = Nov 1993 | pmid = 8281143 | pmc = | doi = 10.1093/hmg/2.11.1829 }}
2. ^1 {{cite journal | vauthors = Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D'Adamo P, Calvo S, Marsano RM, Donnini C, Weiher H, Strisciuglio P, Parini R, Sarzi E, Chan A, DiMauro S, Rötig A, Gasparini P, Ferrero I, Mootha VK, Tiranti V, Zeviani M | title = MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 570–5 | date = May 2006 | pmid = 16582910 | pmc = | doi = 10.1038/ng1765 }}
3. ^1 2 {{cite web | title = Entrez Gene: MPV17 MpV17 mitochondrial inner membrane protein| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4358| accessdate = }}
4. ^1 {{cite journal | vauthors = Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, Hadzic N, Samyn M, Baker A, Rahman S, Stewart H, Morris AA, Seller A, Fratter C, Taylor RW, Poulton J | title = Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene | journal = European Journal of Human Genetics | volume = 22 | issue = 2 | pages = 184–91 | date = Feb 2014 | pmid = 23714749 | doi = 10.1038/ejhg.2013.112 | pmc=3895632}}
5. ^{{cite journal | vauthors = Viscomi C, Spinazzola A, Maggioni M, Fernandez-Vizarra E, Massa V, Pagano C, Vettor R, Mora M, Zeviani M | title = Early-onset liver mtDNA depletion and late-onset proteinuric nephropathy in Mpv17 knockout mice | journal = Human Molecular Genetics | volume = 18 | issue = 1 | pages = 12–26 | date = Jan 2009 | pmid = 18818194 | doi = 10.1093/hmg/ddn309 | pmc=2644642}}
6. ^{{cite journal | vauthors = Bottani E, Giordano C, Civiletto G, Di Meo I, Auricchio A, Ciusani E, Marchet S, Lamperti C, d'Amati G, Viscomi C, Zeviani M | title = AAV-mediated liver-specific MPV17 expression restores mtDNA levels and prevents diet-induced liver failure | journal = Molecular Therapy | volume = 22 | issue = 1 | pages = 10–7 | date = Jan 2014 | pmid = 24247928 | pmc = 3880585 | doi = 10.1038/mt.2013.230 }}
7. ^{{cite journal | vauthors = Casalena G, Krick S, Daehn I, Yu L, Ju W, Shi S, Tsai SY, D'Agati V, Lindenmeyer M, Cohen CD, Schlondorff D, Bottinger EP | title = Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro | journal = American Journal of Physiology. Renal Physiology | volume = 306 | issue = 11 | pages = F1372-80 | date = Jun 2014 | pmid = 24598802 | doi = 10.1152/ajprenal.00608.2013 | pmc=4042102}}
8. ^{{cite journal | vauthors = Antonenkov VD, Isomursu A, Mennerich D, Vapola MH, Weiher H, Kietzmann T, Hiltunen JK | title = The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential | journal = The Journal of Biological Chemistry | volume = 290 | issue = 22 | pages = 13840–61 | date = May 2015 | pmid = 25861990 | doi = 10.1074/jbc.M114.608083 | pmc=4447960}}
9. ^{{cite journal | vauthors = Blakely EL, Butterworth A, Hadden RD, Bodi I, He L, McFarland R, Taylor RW | title = MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle | journal = Neuromuscular Disorders | volume = 22 | issue = 7 | pages = 587–91 | date = Jul 2012 | pmid = 22508010 | doi = 10.1016/j.nmd.2012.03.006 | pmc=3387382}}
10. ^{{cite journal | vauthors = Papeta N, Zheng Z, Schon EA, Brosel S, Altintas MM, Nasr SH, Reiser J, D'Agati VD, Gharavi AG | title = Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice | journal = The Journal of Clinical Investigation | volume = 120 | issue = 11 | pages = 4055–64 | date = Nov 2010 | pmid = 20978358 | doi = 10.1172/JCI43721 | pmc=2964992}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Schenkel J, Zwacka RM, Rutenberg C, Reuter A, Waldherr R, Weiher H | title = Functional rescue of the glomerulosclerosis phenotype in Mpv17 mice by transgenesis with the human Mpv17 homologue | journal = Kidney International | volume = 48 | issue = 1 | pages = 80–4 | date = Jul 1995 | pmid = 7564095 | doi = 10.1038/ki.1995.270 }}
  • {{cite journal | vauthors = Weiher H | title = Glomerular sclerosis in transgenic mice: the Mpv-17 gene and its human homologue | journal = Advances in Nephrology From the Necker Hospital | volume = 22 | issue = | pages = 37–42 | year = 1993 | pmid = 8427063 | doi = }}
  • {{cite journal | vauthors = Iida R, Yasuda T, Tsubota E, Takatsuka H, Masuyama M, Matsuki T, Kishi K | title = M-LP, Mpv17-like protein, has a peroxisomal membrane targeting signal comprising a transmembrane domain and a positively charged loop and up-regulates expression of the manganese superoxide dismutase gene | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 6301–6 | date = Feb 2003 | pmid = 12471025 | doi = 10.1074/jbc.M210886200 }}
  • {{cite journal | vauthors = Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK | title = Systematic identification of human mitochondrial disease genes through integrative genomics | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 576–82 | date = May 2006 | pmid = 16582907 | doi = 10.1038/ng1776 }}
  • {{cite journal | vauthors = Iida R, Yasuda T, Tsubota E, Takatsuka H, Matsuki T, Kishi K | title = Human Mpv17-like protein is localized in peroxisomes and regulates expression of antioxidant enzymes | journal = Biochemical and Biophysical Research Communications | volume = 344 | issue = 3 | pages = 948–54 | date = Jun 2006 | pmid = 16631601 | doi = 10.1016/j.bbrc.2006.04.008 }}
  • {{cite journal | vauthors = Karadimas CL, Vu TH, Holve SA, Chronopoulou P, Quinzii C, Johnsen SD, Kurth J, Eggers E, Palenzuela L, Tanji K, Bonilla E, De Vivo DC, DiMauro S, Hirano M | title = Navajo neurohepatopathy is caused by a mutation in the MPV17 gene | journal = American Journal of Human Genetics | volume = 79 | issue = 3 | pages = 544–8 | date = Sep 2006 | pmid = 16909392 | pmc = 1559552 | doi = 10.1086/506913 }}
  • {{cite journal | vauthors = Wong LJ, Brunetti-Pierri N, Zhang Q, Yazigi N, Bove KE, Dahms BB, Puchowicz MA, Gonzalez-Gomez I, Schmitt ES, Truong CK, Hoppel CL, Chou PC, Wang J, Baldwin EE, Adams D, Leslie N, Boles RG, Kerr DS, Craigen WJ | title = Mutations in the MPV17 gene are responsible for rapidly progressive liver failure in infancy | journal = Hepatology | volume = 46 | issue = 4 | pages = 1218–27 | date = Oct 2007 | pmid = 17694548 | doi = 10.1002/hep.21799 }}
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