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Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease

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Abstract

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype–phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Altif Laboratories supported us for the analysis using three-dimensional human RNF213 modeling.

Funding

This work was supported by JSPS KAKENHI with grant numbers 19K18443 (to Shunsuke Nomura) and 16K10740 (to Hiroyuki Akagawa) and the Hiroto Yoshioka Memorial Medical Research Award (to Shunsuke Nomura).

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Authors and Affiliations

  1. Department of Neurosurgery, Tokyo Women’s Medical University Yachiyo Medical Center, Owadashinden, Yachiyo-Shi, Chiba, 477-96, Japan

    Shunsuke Nomura, Taichi Ishiguro & Akitsugu Kawashima

  2. Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan

    Shunsuke Nomura, Koji Yamaguchi, Akikazu Nakamura, Atsushi Fukui, Yasuo Aihara, Tatsuya Ishikawa, Yosuke Moteki, Kentaro Chiba, Kazutoshi Hashimoto, Shuhei Morita & Takakazu Kawamata

  3. Krembil Brain Institute, University Health Network, University of Toronto, 60 Leonard Ave., Toronto, ON, M5T 0S8, Canada

    Shunsuke Nomura, Sandra Vetiska & Ivan Radovanovic

  4. Institute for Comprehensive Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan

    Hiroyuki Akagawa & Kenko Azuma

  5. Tokyo R&D Center, Altif Laboratories, Inc, Tokyo, Japan

    Fumiko Matsuzawa

  6. Department of Neurosurgery, St. Luke’s International Hospital, Tokyo, Japan

    Yoshikazu Okada & Akitsugu Kawashima

  7. Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada

    Hugo Andrade-Barazarte & Ivan Radovanovic

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  1. Shunsuke Nomura
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Contributions

S.N., H.A., and T.K. designed the study. S.N, H.A, K.A, A.N., and F.M. analyzed the genetic data. S.N., K.Y., A.N., Y.A., T.I., Y.M., K.C., K.H., S.M., T.I., and Y.O. collected and analyzed the clinical data. S.N. and A.F. performed statistical analysis. S.N, H.A., K.A., S.V., H.A., and I.R. contributed to the interpretation and revised the manuscript. All authors reviewed the manuscript.

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Correspondence to Shunsuke Nomura.

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The main results of this work were presented at the World Internet Conference on Moyamoya Disease 2022.

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Nomura, S., Akagawa, H., Yamaguchi, K. et al. Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01194-w

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