ArticleActa neuropathologica2023
Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture.
Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 10 citations in OpenAlex.
- Whole-exome sequencing identifies matrisomal gene associations in monogenic cerebral small vessel disease.Journal of neurology · 2026Article
- Research Progress on the ARHGEF Family in Cardiovascular Diseases.Cell biochemistry and function · 2026Review
- Stromal ARHGEF15 Correlates With Inflammatory EMT and Stromal-Immune Crosstalk During Inflammatory Bowel Disease-To-Colorectal Cancer Progression.Bioinformatics and biology insights · 2026Article
- Advances in genetics and multi-omics for ischemic stroke: from pathogenesis to clinical translation.Frontiers in genetics · 2026Review
- Candidate proteomic indirect-effect signals linking dementia to probable muscle-bone fragility: a UK Biobank cohort study.Frontiers in medicine · 2026Article
- Potential Biological and Genetic Links Between Dementia and Osteoporosis: A Scoping Review.Geriatrics (Basel, Switzerland) · 2025Review
- The pathogenesis of cerebral small vessel disease and vascular cognitive impairment.Physiological reviews · 2025Review
- Osteoporosis Is Associated with Cerebral Small Vessel Disease in Stroke-Free Individuals: A Retrospective Observational Study.Geriatrics (Basel, Switzerland) · 2025Article
- Rare Sequence Variation Underlying Suspected Familial Cerebral Small-Vessel Disease.Journal of the American Heart Association · 2024Article
- Pathophysiology of cerebral small vessel disease: a journey through recent discoveries.The Journal of clinical investigation · 2024Review
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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