Abstract
Introduction
RNF213 mutations have been reported mostly in moyamoya disease (MMD) with varying frequencies across different ethnicities. However, its prevalence in non-MMD adult-onset ischemic stroke is still not well explored.
Aims and objectives
This present study thus aims to screen the most common RNF213 variant (Arg4810Lys, among East Asians) in the Eastern Indian non-MMD ischemic stroke patients and correlate it with long-term progression and prognosis of the patients. The subjects were analyzed for this variant using PCR-RFLP and confirmed using Sanger sequencing method.
Result and conclusion
We have identified Arg4810Lys variant among eleven young-onset familial ischemic stroke patients in heterozygous manner. A positive correlation of the variant with positive family history (P = 0.001), earlier age at onset (P = 0.002), and history of recurrent stroke (P = 0.015) was observed. However, the carriers showed better cognitive performances in memory (P = 0.042) and executive function (P = 0.004). Therefore, we can conclude that Arg4810Lys/RNF213 — a pathogenic variant for young-onset familial ischemic stroke with higher incidence of recurrent events unlike in MMD cases, have no additional impact on cognition among Eastern Indians.
Data availability
The data described in this study are available from the corresponding author upon reasonable request.
References
Hofmeijer J, van Putten MJ (2012) Ischemic cerebral damage: an appraisal of synaptic failure. Stroke 43(2):607–615. https://doi.org/10.1161/STROKEAHA.111.632943
Qin C, Yang S, Chu YH, Zhang H, Pang XW, Chen L, Zhou LQ, Chen M, Tian DS, Wang W (2022) Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 7(1):215. https://doi.org/10.1038/s41392-022-01064-1
Einstad MS, Saltvedt I, Lydersen S, Ursin MH, Munthe-Kaas R, Ihle-Hansen H, Knapskog AB, Askim T, Beyer MK, Næss H, Seljeseth YM, Ellekjær H, Thingstad P (2021) Associations between post-stroke motor and cognitive function: a cross-sectional study. BMC Geriatr 21(1):103. https://doi.org/10.1186/s12877-021-02055-7
Boehme AK, Esenwa C, Elkind MS (2017) Stroke risk factors, genetics, and prevention. Circ Res 120(3):472–495. https://doi.org/10.1161/CIRCRESAHA.116.308398
Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori T, Ono M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S (2011) A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56(1):34–40. https://doi.org/10.1038/jhg.2010.132
Guey S, Kraemer M, Hervé D, Ludwig T, Kossorotoff M, Bergametti F, Schwitalla JC, Choi S, Broseus L, Callebaut I, Genin E, Tournier-Lasserve E, FREX consortium. (2017) Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians. Eur J Hum Genet 25(8):995–1003. https://doi.org/10.1038/ejhg.2017.92
Sugihara M, Morito D, Ainuki S, Hirano Y, Ogino K, Kitamura A, Hirata H, Nagata K (2019) The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. J Cell Biol 218(3):949–960. https://doi.org/10.1083/jcb.201712120
Pollaci G, Gorla G, Potenza A, Carrozzini T, Canavero I, Bersano A, Gatti L (2022) Novel multifaceted roles for RNF213 protein. Int J Mol Sci 23(9):4492. https://doi.org/10.3390/ijms23094492
Park YS, Park HW, Park HS, Ryu CS, Lee JY, Ko EJ, Sung JH, Kim J, Kim OJ, Kim NK (2021) Association of genetic variants of RNF213 with ischemic stroke risk in Koreans. Genes Genomics 43(4):389–397. https://doi.org/10.1007/s13258-020-01022-7
Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M et al (2011) Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 6(7):e22542. https://doi.org/10.1371/journal.pone.0022542
Wang Y, Zhang Z, Wei L, Zhang Q, Zou Z, Yang L, Li D, Shang M, Han C, Mambiya M, Bao X, Li Q, Hao F, Zhang K, Wang H, Liu S, Liu M, Zeng F, Nie F et al (2020) Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology 94(7):e678–e686. https://doi.org/10.1212/WNL.0000000000008901
Kim EH, Yum MS, Ra YS, Park JB, Ahn JS, Kim GH, Goo HW, Ko TS, Yoo HW (2016) Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease. J Neurosurg 124(5):1221–1227. https://doi.org/10.3171/2015.4.JNS142900
K A, Shafeeque CM, Sudhir JB, Banerjee M, P N S Ethnic variation and the relevance of homozygous RNF 213 p.R4810.K variant in the phenotype of Indian Moya moya disease. PLoSOne 15(12):e0243925. https://doi.org/10.1371/journal.pone.0243925
Sriram TG, Chandrashekar CR, Isaac MK, Shanmugham V (1989) The General Health Questionnaire (GHQ). Comparison of the English version and a translated Indian version. Soc Psychiatry Psychiatr Epidemiol 24(6):317–320. https://doi.org/10.1007/BF01788035
Johns MB Jr, Paulus-Thomas JE (1989) Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal Biochem 180(2):276–278
Lin J, Sheng W (2018) RNF213 variant diversity predisposes distinct populations to dissimilar cerebrovascular diseases. Biomed Res Int 2018:6359174. https://doi.org/10.1155/2018/6359174
Kamimura T, Okazaki S, Morimoto T, Kobayashi H, Harada K, Tomita T, Higashiyama A, Yoshimoto T, Takahashi JC, Nakagawara J, Koga M, Toyoda K, Maruyama H, Koizumi A, Ihara M (2019) Prevalence of RNF213 p.R4810K variant in early-onset stroke with intracranial arterial stenosis. Stroke 50(6):1561–1563. https://doi.org/10.1161/STROKEAHA.118.024712
Acknowledgements
The authors thank the patient, family members, and healthy individuals who participated in the study.
Funding
This study was supported by grants from the Department of Science & Technology, Government of India, under Cognitive Science Research Initiative Programme DST/CSRI-PDF/2021/12 and DST/CSRI-P/2017/22.
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Dipanwita Sadhukhan and Arindam Biswas were responsible for the concept, study design, and manuscript preparation. Atanu Biswas, Biman Kanti Ray, Tapas Kumar Banerjee, and Gargi Podder were responsible for the diagnosis, recruitment, clinical evaluation, and blood collection for all study subjects. Parama Mitra, Smriti Mishra, and Arunima Roy were responsible for experimental work and manuscript preparation. Subhra Prakashu Hui was responsible for manuscript preparation. All authors read the draft, provided their inputs, and agreed on the final version of the manuscript.
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Sadhukhan, ., Mitra, P., Mishra, S. et al. Arg4810Lys mutation in RNF213 among Eastern Indian non-MMD ischemic stroke patients: a genotype–phenotype correlation. Neurol Sci 45, 315–319 (2024). https://doi.org/10.1007/s10072-023-07051-w
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DOI: https://doi.org/10.1007/s10072-023-07051-w