Clarification of the molecular pathogenesis of familial moyamoya disease and the establishment of preventive medicine for cerebrovascular disease

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Mysterin was recently identified as the susceptibility gene for moyamoya disease and its coding variant, p.R4810K, was identified as a common founder variant in East Asian countries. Induced pluripotent stem cells (iPSCs) were established from unaffected fibroblast donors with wild-type mysterin alleles and carriers/patients with one or two mysterin p.R4810K alleles. Angiogenic activities of iPSC-derived vascular endothelial cells (iPSECs) from patients and carriers were lower than those from wild-type subjects. Furthermore, their gene expression profiles revealed that mitotic phase-associated genes, including Securin, were down-regulated in carriers and patients. Overexpression of mysterin p.R4810K induced MAD2 functional inhibition, delay of mitotic progression, mitotic abnormalities, and an increased risk of genomic instability. Thus, mysterin p.R4810K causes endothelial cell dysfunction and is considered to lead to stenosis of cerebral blood vessels.