Skip to main content

Advertisement

SpringerLink
Log in

RNF213 p.Arg4810Lys Heterozygosity in Moyamoya Disease Indicates Early Onset and Bilateral Cerebrovascular Events

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

An Author Correction to this article was published on 26 November 2021

This article has been updated

Abstract

The relationship between RNF213 c.14429G > A (p.Arg4810Lys) heterozygous variants and clinical manifestation in patients with Moyamoya disease (MMD) remains unclear. We performed a retrospective cohort analysis to clarify the genotype–phenotype correlation of this RNF213 hotspot variant in MMD patients, especially between wild-type (GG) and heterozygous (GA) genotypes. Clinical and genetic data were obtained from patients diagnosed with MMD in our institutions between October 2011 and November 2020. Clinical data included age, sex, neurological status at diagnosis, medical history, smoking history, alcohol intake, and family history. Of the 225 enrolled patients, 160 (71.1%) were symptomatic, 3 (1.3%) had the homozygous variant, and 149 (66.2%) had the heterozygous variant (GA). Analysis of all enrolled patients showed that the GA group was prone to present bilateral symptoms (p = 0.008) and progressive status (Suzuki grade ≥ 4; p = 0.017). Analysis limited to symptomatic patients revealed that the GA group had bilateral symptoms (p = 0.017), younger age at onset (p = 0.043), and, in particular, a higher proportion of onset before 25 years of age (p = 0.021). Multivariate logistic regression analysis of overall patients revealed that earlier age at diagnosis (p < 0.001, OR 0.936, 95% CI 0.914–0.959) and GA group (p = 0.017, OR 3.326, 95%CI 1.237–8.941) were significantly associated with bilateral symptoms. MMD patients diagnosed at a young age with the RNF213 heterozygous variant should be followed up with consideration of possible contralateral stroke if one hemisphere is already symptomatic or of early cerebrovascular events if bilateral hemispheres are asymptomatic.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Change history

References

  1. Suzuki J, Takaku A. Cerebrovascular, “Moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20:288–99. https://doi.org/10.1001/archneur.1969.00480090076012.

    Article  CAS  PubMed  Google Scholar 

  2. 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;56:34–40. https://doi.org/10.1038/jhg.2010.132.

    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:e22542. https://doi.org/10.1371/journal.pone.0022542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Otten EG, Werner E, Crespillo-Casado A, Boyle KB, Dharamdasani V, Pathe C, et al. Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature. 2021;594:111–6. https://doi.org/10.1038/s41586-021-03566-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S. A new horizon of Moyamoya disease and associated health risks explored through RNF213. Environ Health Prev Med. 2016;21:55–70. https://doi.org/10.1007/s12199-015-0498-7.

    Article  CAS  PubMed  Google Scholar 

  6. 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;78:803–10. https://doi.org/10.1212/WNL.0b013e318249f71f.

    Article  CAS  PubMed  Google Scholar 

  7. Miyawaki S, Imai H, Takayanagi S, Mukasa A, Nakatomi H, Saito N. Identification of a genetic variant common to Moyamoya disease and intracranial major artery stenosis/occlusion. Stroke. 2012;43:3371–4. https://doi.org/10.1161/STROKEAHA.112.663864.

    Article  PubMed  Google Scholar 

  8. Miyawaki S, Imai H, Shimizu M, Yagi S, Ono H, Mukasa A, et al. Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion. Stroke. 2013;44:2894–7. https://doi.org/10.1161/STROKEAHA.113.002477.

    Article  CAS  PubMed  Google Scholar 

  9. Bang OY, Ryoo S, Kim SJ, Yoon CH, Cha J, Yeon JY, et al. Adult Moyamoya disease: a burden of intracranial stenosis in East Asians? PLoS One. 2015;10:e0130663. https://doi.org/10.1371/journal.pone.0130663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim EH, Yum MS, Ra YS, Park JB, Ahn JS, Kim GH, et al. Importance of RNF213 polymorphism on clinical features and long-term outcome in Moyamoya disease. J Neurosurg. 2016;124:1221–7. https://doi.org/10.3171/2015.4.JNS142900.

    Article  CAS  PubMed  Google Scholar 

  11. Nomura S, Yamaguchi K, Akagawa H, Kawashima A, Moteki Y, Ishikawa T, et al. Genotype-phenotype correlation in long-term cohort of Japanese patients with Moyamoya disease. Cerebrovasc Dis. 2019;47:105–11. https://doi.org/10.1159/000499699.

    Article  CAS  PubMed  Google Scholar 

  12. YS Park HW Park HS Park CS Ryu JY Lee EJ Ko et al Association of genetic variants of RNF213 with ischemic stroke risk in Koreans Genes Genomics. 2021 https://doi.org/10.1007/s13258-020-01022-7

  13. Wu Z, Jiang H, Zhang L, Xu X, Zhang X, Kang Z, et al. Molecular analysis of RNF213 gene for Moyamoya disease in the Chinese Han population. PLoS One. 2012;7:e48179. https://doi.org/10.1371/journal.pone.0048179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang X, Zhang Z, Liu W, Xiong Y, Sun W, Huang X, et al. Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects. Gene. 2013;526:437–42. https://doi.org/10.1016/j.gene.2013.05.083.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Q, Liu Y, Zhang D, Wang R, Zhang Y, Wang S, et al. RNF213 as the major susceptibility gene for Chinese patients with Moyamoya disease and its clinical relevance. J Neurosurg. 2017;126:1106–13. https://doi.org/10.3171/2016.2.JNS152173.

    Article  CAS  PubMed  Google Scholar 

  16. Wang Y, Zhang Z, Wei L, Zhang Q, Zou Z, Yang L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese Moyamoya disease. Neurology. 2020;94:e678–86. https://doi.org/10.1212/WNL.0000000000008901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim WH, Kim SD, Nam MH, Jung JM, Jin SW, Ha SK, et al. Posterior circulation involvement and collateral flow pattern in Moyamoya disease with the RNF213 polymorphism. Childs Nerv Syst. 2019;35:309–14. https://doi.org/10.1007/s00381-018-3985-5.

    Article  PubMed  Google Scholar 

  18. Ge P, Ye X, Liu X, Deng X, Wang J, Wang R, et al. Association between p.R4810K variant and postoperative collateral formation in patients with Moyamoya disease. Cerebrovasc Dis. 2019;48:77–84. https://doi.org/10.1159/000503250.

    Article  CAS  PubMed  Google Scholar 

  19. Y Wang L Yang X Wang F Zeng K Zhang Q Zhang et al Meta-analysis of genotype and phenotype studies confirms predictive roles of the RNF213 p.R4810K for Moyamoya disease Eur J Neurol. 2020 https://doi.org/10.1111/ene.14635

  20. Research Committee on the P, Treatment of Spontaneous Occlusion of the Circle of W, Health Labour Sciences Research Grant for Research on Measures for Infractable D. Guidelines for diagnosis and treatment of Moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir. 2012;52:245–66.

    Article  Google Scholar 

  21. Tominaga T, Suzuki N, Miyamoto S, Koizumi A, Kuroda S, Takahashi JC, et al. Recommendations for the management of Moyamoya disease: a statement from research committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) [2nd Edition]. Surgery for Cerebral Stroke. 2018;46:1–24. https://doi.org/10.2335/scs.46.1.

    Article  Google Scholar 

  22. Ge P, Ye X, Liu X, Deng X, Wang R, Zhang Y, et al. Association Between p.R4810K Variant and long-term clinical outcome in patients with Moyamoya disease. Front Neurol. 2019;10:662. https://doi.org/10.3389/fneur.2019.00662.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chang SA, Song JS, Park TK, Yang JH, Kwon WC, Kim SR, et al. Nonsyndromic peripheral pulmonary artery stenosis is associated with homozygosity of RNF213 p.Arg4810Lys regardless of co-occurrence of Moyamoya disease. Chest. 2018;153:404–13. https://doi.org/10.1016/j.chest.2017.09.023.

    Article  PubMed  Google Scholar 

  24. Hirano Y, Miyawaki S, Imai H, Hongo H, Ohara K, Dofuku S, et al. Association between the onset pattern of adult Moyamoya disease and risk factors for stroke. Stroke. 2020;51:3124–8. https://doi.org/10.1161/STROKEAHA.120.030653.

    Article  CAS  PubMed  Google Scholar 

  25. Liao X, Deng J, Dai W, Zhang T, Yan J. Rare variants of RNF213 and Moyamoya/non-Moyamoya intracranial artery stenosis/occlusion disease risk: a meta-analysis and systematic review. Environ Health Prev Med. 2017;22:75. https://doi.org/10.1186/s12199-017-0680-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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. https://doi.org/10.1016/j.brainres.2014.01.011.

    Article  CAS  PubMed  Google Scholar 

  27. 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;432:519–25. https://doi.org/10.1016/j.bbrc.2013.02.015.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a Grant-in-Aid for Scientific Research (B; No. 21H03041) to Dr. Saito and a Grant-in-Aid for Scientific Research (C; No. 19K09473) to Dr. Miyawaki from the Ministry of Education, Culture, Sports, Science and Technology, grants from the Mitsui Life Social Welfare Foundation to Dr. Miyawaki, and grants from the MSD Life Science Foundation (Public Interest Incorporated Foundation) to Dr. Miyawaki.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Daiichiro Ishigami, Satoru Miyawaki, Hiroki Hongo, Shogo Dofuku, Kenta Ohara, Yu Teranishi, Satoshi Koizumi, Yudai Hirano, Masafumi Segawa, Hirofumi Nakatomi & Nobuhito Saito

  2. Department of Neurosurgery, JCHO Tokyo Shinjuku Medical Center, Tokyo, Japan

    Hideaki Imai

  3. Department of Neurosurgery, Kanto Neurosurgery Hospital, Saitama, Japan

    Masahiro Shimizu

  4. Department of Neurosurgery, Kyorin University, Tokyo, Japan

    Daisuke Shimada & Hirofumi Nakatomi

  5. Department of Neurosurgery, Fuji Brain Institute and Hospital, Shizuoka, Japan

    Hideaki Ono

Authors
  1. Daiichiro Ishigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Satoru Miyawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideaki Imai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiro Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroki Hongo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shogo Dofuku
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenta Ohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu Teranishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daisuke Shimada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satoshi Koizumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hideaki Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yudai Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Masafumi Segawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hirofumi Nakatomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nobuhito Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoru Miyawaki.

Ethics declarations

Ethics Approval and Consent to Participate

This study was approved by the Human Genome, Gene Analysis Research Ethics Committee of the Faculty of Medicine, The University of Tokyo (approval number G10026; approval date, September 12, 2011). The Ethics Committee of Kanto Neurosurgical Hospital also approved this study (approval date, June 23, 2012). Written informed consent was obtained from all participants or parents/legal guardians for participants under age at 18.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 964 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ishigami, D., Miyawaki, S., Imai, H. et al. RNF213 p.Arg4810Lys Heterozygosity in Moyamoya Disease Indicates Early Onset and Bilateral Cerebrovascular Events. Transl. Stroke Res. 13, 410–419 (2022). https://doi.org/10.1007/s12975-021-00956-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-021-00956-8

Keywords

Search

Navigation