{
  "abstract": "Background The p.R4810K founder mutation in the RNF213 gene confers susceptibility to moyamoya disease (MMD) and non-MMD intracranial artery disease. However, penetrance is incomplete, and the underlying molecular mechanism remains unknown.Methods and results Transcriptome analysis of peripheral blood was conducted with nine MMD patients and five unaffected mutation carriers from four familial MMD pedigrees. Bayesian network analysis identified upregulated gene modules associated with lipid metabolism and leucocyte development (including GATA2 and SLC45A3), and epidermal growth factor receptor (EGFR) signalling (UBTD1). It also identified downregulated gene modules related to mitochondrial ribosomal proteins (RPS3A and RPL26), and cytotoxic T cell immunity (GZMA and TRGC1). The GATA2 network was replicated through weighted gene co-expression network analysis and further examined in a case–control study, comprising 43 MMD patients, 16 non-MMD patients, 19 unaffected carriers and 35 healthy controls. GATA2 exhibited a significant linear correlation with SLC45A3 and was significantly higher in MMD patients compared with age-matched and sex-matched unaffected carriers or wild-type controls. Among patients with the p.R4810K mutation, higher GATA2 expression was associated with an earlier age of onset, bilateral involvement and symptomatic disease onset.Conclusions Peripheral blood GATA2 expression was associated with increased penetrance of the RNF213 mutation and more severe clinical manifestations in MMD.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Department of Artificial Intelligence in Healthcare and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Department of Biomedical Data Intelligence, Kyoto University Graduate School of Medicine, Kyoto, Japan"
      ],
      "name": "Yohei Mineharu"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Department of Neurosurgery, Koseikai Takeda Hospital, Kyoto, Japan"
      ],
      "name": "Takahiko Kamata"
    },
    {
      "affiliations": [
        "Department of Biomedical Data Intelligence, Kyoto University Graduate School of Medicine, Kyoto, Japan"
      ],
      "name": "Mei Tomoto"
    },
    {
      "affiliations": [
        "Department of Biomedical Data Intelligence, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan"
      ],
      "name": "Noriaki Sato"
    },
    {
      "affiliations": [
        "Innovation Center for Health Promotion, Hirosaki University, Hirosaki, Japan"
      ],
      "name": "Yoshinori Tamada"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"
      ],
      "name": "Takeshi Funaki"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Department of Neurosurgery, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan"
      ],
      "name": "Yuki Oichi"
    },
    {
      "affiliations": [
        "Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan"
      ],
      "name": "Kouji H Harada"
    },
    {
      "affiliations": [
        "Social Health Medicine Welfare Laboratory, Public Interest Incorporated Association Kyoto Hokenkai, Kyoto, Japan"
      ],
      "name": "Akio Koizumi"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan",
        "Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan"
      ],
      "name": "Tetsuaki Kimura"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Mishima, Japan"
      ],
      "name": "Ituro Inoue"
    },
    {
      "affiliations": [
        "Department of Artificial Intelligence in Healthcare and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Department of Biomedical Data Intelligence, Kyoto University Graduate School of Medicine, Kyoto, Japan",
        "Biomedical Computational Intelligence Unit, HPC- and AI-Driven Drug Development Platform Division, RIKEN Center for Computational Science, Kobe, Japan"
      ],
      "name": "Yasushi Okuno"
    },
    {
      "affiliations": [
        "Moyamoya Disease Support Center, Stroke Support Center, Kyoto University Hospital, Kyoto, Japan"
      ],
      "name": "Susumu Miyamoto"
    },
    {
      "affiliations": [
        "Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan"
      ],
      "name": "Yoshiki Arakawa"
    }
  ],
  "title": "Peripheral blood GATA2 expression impacts RNF213 mutation penetrance and clinical severity in moyamoya disease",
  "uid": "e519a7f1-22cc-53a4-a454-dbce2e71bd35"
}