{
    "abstract": "Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-\u03b22. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-\u03b22 inactivation. An activity assay confirmed a significant increase in TGF-\u03b22/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-\u03b22 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.",
    "authors": [
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.",
            "firstname": "Zheng",
            "initials": "Z",
            "lastname": "Wang"
        },
        {
            "affiliation": "Division of Endocrinology and Hypertension, Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.",
            "firstname": "Mitsuhiro",
            "initials": "M",
            "lastname": "Kometani"
        },
        {
            "affiliation": "Pediatric Bone Clinic, Orthopaedic Department, Tel Aviv Medical Center, Tel Aviv, Israel.",
            "firstname": "Leonid",
            "initials": "L",
            "lastname": "Zeitlin"
        },
        {
            "affiliation": "Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.",
            "firstname": "Yael",
            "initials": "Y",
            "lastname": "Wilnai"
        },
        {
            "affiliation": "Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.",
            "firstname": "Akira",
            "initials": "A",
            "lastname": "Kinoshita"
        },
        {
            "affiliation": "Department of Human Genetics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.",
            "firstname": "Koh-Ichiro",
            "initials": "KI",
            "lastname": "Yoshiura"
        },
        {
            "affiliation": "Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Toon, Japan.",
            "firstname": "Hiroko",
            "initials": "H",
            "lastname": "Ninomiya"
        },
        {
            "affiliation": "Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Toon, Japan.",
            "firstname": "Takeshi",
            "initials": "T",
            "lastname": "Imamura"
        },
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.",
            "firstname": "Long",
            "initials": "L",
            "lastname": "Guo"
        },
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.",
            "firstname": "Jingyi",
            "initials": "J",
            "lastname": "Xue"
        },
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.",
            "firstname": "Li",
            "initials": "L",
            "lastname": "Yan"
        },
        {
            "affiliation": "Division of Medical Genetics, Saitama Children's Medical Genetics, Saitama, Japan.",
            "firstname": "Hirofumi",
            "initials": "H",
            "lastname": "Ohashi"
        },
        {
            "affiliation": "Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.",
            "firstname": "Yann",
            "initials": "Y",
            "lastname": "Pretemer"
        },
        {
            "affiliation": "Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.",
            "firstname": "Shunsuke",
            "initials": "S",
            "lastname": "Kawai"
        },
        {
            "affiliation": "Department of Biochemistry, Yokohama City University, Yokohama, Japan.",
            "firstname": "Masaaki",
            "initials": "M",
            "lastname": "Shiina"
        },
        {
            "affiliation": "Department of Biochemistry, Yokohama City University, Yokohama, Japan.",
            "firstname": "Kazuhiro",
            "initials": "K",
            "lastname": "Ogata"
        },
        {
            "affiliation": "Department of Molecular, Cell, and Developmental Biology, Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, CA, USA.",
            "firstname": "Daniel H",
            "initials": "DH",
            "lastname": "Cohn"
        },
        {
            "affiliation": "Department of Human Genetics, Yokohama City University, Yokohama, Japan.",
            "firstname": "Naomichi",
            "initials": "N",
            "lastname": "Matsumoto"
        },
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.",
            "firstname": "Gen",
            "initials": "G",
            "lastname": "Nishimura"
        },
        {
            "affiliation": "Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.",
            "firstname": "Junya",
            "initials": "J",
            "lastname": "Toguchida"
        },
        {
            "affiliation": "Department of Human Genetics, Yokohama City University, Yokohama, Japan.",
            "firstname": "Noriko",
            "initials": "N",
            "lastname": "Miyake"
        },
        {
            "affiliation": "Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. sikegawa@yahoo.co.jp.",
            "firstname": "Shiro",
            "initials": "S",
            "lastname": "Ikegawa"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.",
    "doi": "10.1038/s10038-024-01274-1\n10.1002/ajmg.a.61366\n10.1136/jmg.2005.033522\n10.1086/302728\n10.1038/79128\n10.1034/j.1399-0004.2001.590310.x\n10.1002/ajmg.10079\n10.1038/jhg.2016.157\n10.1101/gr.107524.110\n10.1093/nar/gkq603\n10.1038/nmeth.3213\n10.1038/nature10152\n10.1093/nar/gki387\n10.1074/jbc.M208857200\n10.1038/nmeth.1591\n10.1371/journal.pone.0112291\n10.1074/jbc.M110.110288\n10.1074/jbc.C000859200\n10.1126/science.3487831\n10.1038/ng1001-117",
    "journal": "Journal of human genetics",
    "keywords": [],
    "methods": null,
    "publication_date": "2024-07-17",
    "pubmed_id": "39014191\n31633310\n15894597\n10631145\n10973241\n11260231\n11807860\n28123176\n20644199\n20601685\n25549265\n21677751\n15980494\n12493741\n21460823\n25464501\n20308061\n11278244\n3487831\n11586292",
    "results": null,
    "title": "Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati-Engelmann disease type II.",
    "xml": "<Element 'PubmedArticle' at 0x7885026a1440>"
}