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Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture

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Abstract

Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the ARHGEF15 gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the ARHGEF15 gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the ARHGEF15 mutation carriers. In vitro experiments indicated that ARHGEF15 mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/β-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the ARHGEF15 gene cause CSVD accompanied by osteoporotic fracture.

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

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (no. 82122022, 82171248 and 81873791), the Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357), the Natural Science Foundation of Henan Province for Distinguished Young Scholars (no.222300420017), the Henan Province Young and Middle-Aged Health Science and Technology Innovation Talent Project (YXKC2020033), and the National Key Research and Development Program of China (2021YFC2502100 and 2021YFC2501200).

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Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Xuebing Ding, Yongkang Chen, Cancan Guo, Yu Fu, Chi Qin, Qingyong Zhu, Jiuqi Wang, Rui Zhang, Haiyan Tian, Renyi Feng, Han Liu, Dongxiao Liang, Junfang Teng & Xuejing Wang

  2. Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, China

    Xuebing Ding, Yongkang Chen, Cancan Guo, Yu Fu, Chi Qin, Qingyong Zhu, Jiuqi Wang, Rui Zhang, Haiyan Tian, Renyi Feng, Han Liu, Dongxiao Liang, Junfang Teng & Xuejing Wang

  3. Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases &, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China

    Guanghui Wang

  4. Bioinformatics Center, National Clinical Research Centre for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China

    Jinchen Li

  5. The First Affiliated Hospital, Multi-Omics Research Center for Brain Disorders, Hengyang Medical School, University of South China, Hengyang, China

    Beisha Tang

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Contributions

XBD, XJW conceived and designed the experiments; XBD coordinated the whole project; XBD, XJW, BST, JCL were responsible for the initial assessment and diagnosing of patients; YKC, CCG, YF were responsible for assessing and documenting the patients’ information; YKC, RZ performed cell cultures; JQW, CQ, RZ, QYZ performed image analysis; HYT, RYF, HL conducted behavioral tests; DXL performed immunostaining; YKC, CCG performed WB analysis; YKC, CCG, YF performed statistical analysis; GHW, JFT provided technical support; XBD, XJW, BST, JCL participated in final data analysis and interpretation; XBD, XJW, YKC carried out most of the writing with input from other authors. All authors discussed the results and commented on the manuscript.

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Correspondence to Jinchen Li, Beisha Tang or Xuejing Wang.

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Ding, X., Chen, Y., Guo, C. et al. Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture. Acta Neuropathol 145, 681–705 (2023). https://doi.org/10.1007/s00401-023-02560-6

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