Skip to main content
SpringerLink
Log in

Molecular Biology of Mysterin/RNF213

  • Chapter
  • First Online:
Moyamoya Disease Explored Through RNF213

  • 541 Accesses

Abstract

Mysterin, also called RNF213, is a large intracellular protein (591 kDa) that contains two tandem AAA+ ATPase modules and a RING finger ubiquitin ligase motif. Although its physiological role remains unclear, mysterin is considered to be the most prominent susceptibility factor for moyamoya disease, an idiopathic cerebrovascular disorder in humans. The C-terminal R4810K mutation of mysterin significantly increases the risk of moyamoya disease, but its molecular effect on the mysterin protein remains largely unclear. Multiple studies have explored the physiological and pathological roles of mysterin at the molecular, cellular, and tissue/individual levels since its identification and molecular cloning, and the results obtained to date suggest that mysterin is involved in angiogenesis and/or endothelial cell behavior; however, no unified and precise understanding has yet been established. In this chapter, we provide an overview of mysterin’s genomic composition, enzymatic activities, structure, and mutant phenotypes in vitro and in vivo and discuss its potential physiological and pathological roles from the standpoint of molecular biology.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, et al. Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke. 2000;31(4):930–5.

    Article  CAS  PubMed  Google Scholar 

  2. Mineharu Y, Liu W, Inoue K, Matsuura N, Inoue S, Takenaka K, et al. Autosomal dominant moyamoya disease maps to chromosome 17q25.3. Neurology. 2008;70(24 Pt 2):2357–63. doi:10.1212/01.wnl.0000291012.49986.f9.

    Article  CAS  PubMed  Google Scholar 

  3. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542. doi:10.1371/journal.pone.0022542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, et al. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet. 2011;56(1):34–40. doi:10.1038/jhg.2010.132.

    Article  CAS  PubMed  Google Scholar 

  5. Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7(11):1056–66. doi:10.1016/S1474-4422(08)70240-0.

    Article  PubMed  Google Scholar 

  6. Morito D, Nishikawa K, Hoseki J, Kitamura A, Kotani Y, Kiso K, et al. Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ ATPase, which dynamically changes its oligomeric state. Sci Rep. 2014;4:4442. doi:10.1038/srep04442.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Moritake H, Shimonodan H, Marutsuka K, Kamimura S, Kojima H, Nunoi H. C-MYC rearrangement may induce an aggressive phenotype in anaplastic lymphoma kinase positive anaplastic large cell lymphoma: identification of a novel fusion gene ALO17/C-MYC. Am J Hematol. 2002;86(1):75–8. doi:10.1002/ajh.21887.

    Article  Google Scholar 

  8. Li B, Dettai A, Cruaud C, Couloux A, Desoutter-Meniger M, Lecointre G. RNF213, a new nuclear marker for acanthomorph phylogeny. Mol Phylogenet Evol. 2009;50(2):345–63. doi:10.1016/j.ympev.2008.11.013.

    Article  CAS  PubMed  Google Scholar 

  9. Hanson PI, Whiteheart SW. AAA+ proteins: have engine, will work. Nat Rev Mol Cell Biol. 2005;6(7):519–29. doi:10.1038/nrm1684.

    Article  CAS  PubMed  Google Scholar 

  10. Ogura T, Wilkinson AJ. AAA+ superfamily ATPases: common structure–diverse function. Genes Cells. 2001;6(7):575–97.

    Article  CAS  PubMed  Google Scholar 

  11. Oguchi Y, Kummer E, Seyffer F, Berynskyy M, Anstett B, Zahn R, et al. A tightly regulated molecular toggle controls AAA+ disaggregase. Nat Struct Mol Biol. 2012;19(12):1338–46. doi:10.1038/nsmb.2441.

    Article  CAS  PubMed  Google Scholar 

  12. Joazeiro CA, Weissman AM. RING finger proteins: mediators of ubiquitin ligase activity. Cell. 2000;102(5):549–52.

    Article  CAS  PubMed  Google Scholar 

  13. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79. doi:10.1146/annurev.biochem.67.1.425.

    Article  CAS  PubMed  Google Scholar 

  14. Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. J Cell Sci. 2016;129(5):875–80. doi:10.1242/jcs.183954.

    Article  CAS  PubMed  Google Scholar 

  15. Borden KL, Freemont PS. The RING finger domain: a recent example of a sequence-structure family. Curr Opin Struct Biol. 1996;6(3):395–401.

    Article  CAS  PubMed  Google Scholar 

  16. van de Weijer ML, Bassik MC, Luteijn RD, Voorburg CM, Lohuis MA, Kremmer E, et al. A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation. Nat Commun. 2014;5:3832. doi:10.1038/ncomms4832.

    PubMed  PubMed Central  Google Scholar 

  17. Wen J, Sun X, Chen H, Liu H, Lai R, Li J, et al. Mutation of rnf213a by TALEN causes abnormal angiogenesis and circulation defects in zebrafish. Brain Res. 1644;2016:70–8. doi:10.1016/j.brainres.2016.04.051.

    Google Scholar 

  18. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9(6):685–93. doi:10.1038/nm0603-685.

    Article  CAS  PubMed  Google Scholar 

  19. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003;161(6):1163–77. doi:10.1083/jcb.200302047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Torres-Vazquez J, Gitler AD, Fraser SD, Berk JD, Van NP, Fishman MC, et al. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev Cell. 2004;7(1):117–23. doi:10.1016/j.devcel.2004.06.008.

    Article  CAS  PubMed  Google Scholar 

  21. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, et al. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 2007;445(7129):776–80. doi:10.1038/nature05571.

    Article  PubMed  Google Scholar 

  22. Kobayashi H, Yamazaki S, Takashima S, Liu W, Okuda H, Yan J, et al. Ablation of Rnf213 retards progression of diabetes in the Akita mouse. Biochem Biophys Res Commun. 2013;432(3):519–25. doi:10.1016/j.bbrc.2013.02.015.

    Article  CAS  PubMed  Google Scholar 

  23. Sonobe S, Fujimura M, Niizuma K, Nishijima Y, Ito A, Shimizu H, et al. Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain Res. 2014;1552:64–71. doi:10.1016/j.brainres.2014.01.011.

    Article  CAS  PubMed  Google Scholar 

  24. Sonobe S, Fujimura M, Niizuma K, Fujimura T, Furudate S, Nishijima Y, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport. 2014;25(18):1442–6. doi:10.1097/WNR.0000000000000289.

    Article  CAS  PubMed  Google Scholar 

  25. Ito A, Fujimura M, Niizuma K, Kanoke A, Sakata H, Morita-Fujimura Y, et al. Enhanced post-ischemic angiogenesis in mice lacking RNF213; a susceptibility gene for moyamoya disease. Brain Res. 2015;1594:310–20. doi:10.1016/j.brainres.2014.11.014.

    Article  CAS  PubMed  Google Scholar 

  26. Hitomi T, Habu T, Kobayashi H, Okuda H, Harada KH, Osafune K, et al. Downregulation of Securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients. Biochem Biophys Res Commun. 2013;438(1):13–9. doi:10.1016/j.bbrc.2013.07.004.

    Article  CAS  PubMed  Google Scholar 

  27. Hitomi T, Habu T, Kobayashi H, Okuda H, Harada KH, Osafune K, et al. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality. Biochem Biophys Res Commun. 2013;439(4):419–26. doi:10.1016/j.bbrc.2013.08.067.

    Article  CAS  PubMed  Google Scholar 

  28. Ohkubo K, Sakai Y, Inoue H, Akamine S, Ishizaki Y, Matsushita Y, et al. Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci Rep. 2015;5:13191. doi:10.1038/srep13191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kotani Y, Morito D, Yamazaki S, Ogino K, Kawakami K, Takashima S, et al. Neuromuscular regulation in zebrafish by a large AAA+ ATPase/ubiquitin ligase, mysterin/RNF213. Sci Rep. 2015;5:16161. doi:10.1038/srep16161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Scholz B, Korn C, Wojtarowicz J, Mogler C, Augustin I, Boutros M, et al. Endothelial RSPO3 controls vascular stability and pruning through Non-canonical WNT/Ca(2+)/NFAT signaling. Dev Cell. 2016;36(1):79–93. doi:10.1016/j.devcel.2015.12.015.

    Article  CAS  PubMed  Google Scholar 

  31. Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, et al. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol. 2016;18(7):803–13. doi:10.1038/ncb3376.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, et al. Biochemical and functional characterization of RNF213 (Mysterin) R4810K, a susceptibility mutation of moyamoya disease, in angiogenesis in vitro and in vivo. J Am Heart Assoc. 2015;4(7) doi:10.1161/JAHA.115.002146.

  33. Kanoke A, Fujimura M, Niizuma K, Ito A, Sakata H, Sato-Maeda M, et al. Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213, the susceptibility gene for moyamoya disease. Brain Res. 2015;1624:497–505. doi:10.1016/j.brainres.2015.07.039.

    Article  CAS  PubMed  Google Scholar 

  34. Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803–10. doi:10.1212/WNL.0b013e318249f71f.

    Article  CAS  PubMed  Google Scholar 

  35. Mineharu Y, Takenaka K, Yamakawa H, Inoue K, Ikeda H, Kikuta KI, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry. 2006;77(9):1025–9. doi:10.1136/jnnp.2006.096040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

This work was supported by MEXT JSPS/KAKENHI (15K07062 and 15H01546 to D.M. and 24227009 to K.N.).

Author information

Authors and Affiliations

  1. Institute of Protein Dynamics, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto, 603-8555, Japan

    Daisuke Morito & Kazuhiro Nagata

  2. CREST, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan

    Daisuke Morito & Kazuhiro Nagata

  3. Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan

    Kazuhiro Nagata

Authors
  1. Daisuke Morito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhiro Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Daisuke Morito or Kazuhiro Nagata .

Editor information

Editors and Affiliations

  1. Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Akio Koizumi

  2. Faculty of Life Sciences, Kyoto Sangyo University, Kyoto, Japan

    Kazuhiro Nagata

  3. Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Kiyohiro Houkin

  4. Department of Neurosurgery, Tohoku University School of Medicine, Sendai, Japan

    Teiji Tominaga

  5. Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Susumu Miyamoto

  6. Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan

    Shigeo Kure

  7. CHU Paris‐GH St‐Louis Lariboisière F‐Widal, Hôpital Lariboisière, Paris, France

    Elizabeth Tournier-Lasserve

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Morito, D., Nagata, K. (2017). Molecular Biology of Mysterin/RNF213. In: Koizumi, A., et al. Moyamoya Disease Explored Through RNF213. Current Topics in Environmental Health and Preventive Medicine. Springer, Singapore. https://doi.org/10.1007/978-981-10-2711-6_4

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-2711-6_4

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-2710-9

  • Online ISBN: 978-981-10-2711-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation