Systematic sequence analysis for early onset skeletal dysplasia

• Project/Area Number: 17K16710
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Wang Zheng 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (90794313)
• Research Collaborator: GUO long ; IKEGAWA shiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 骨系統疾患 / 単一遺伝子病 / 遺伝子変異 / ゲノム解析 / エキソーム解析 / 分子病態 / 遺伝子診断 / 原因遺伝子 / シーケンス解析 / Exome解析 / WES

Outline of Final Research Achievements

Skeletal dysplasia refers to a group of diseases that affect the skeletal system including bone and joint. More than 400 diseases are included in this disease category and most of them are rare, monogenic diseases. A large part of skeletal dysplasia develops early in life. Those early-onset skeletal dysplasias are difficult to diagnose and treat. The purpose of the present study is to identify the disease genes for the early-onset skeletal dysplasia. By a large-scale sequence analyses in collaboration of experts all over the world, including whole-exome sequencing, we have succeeded in identification of the disease genes for the first in the world, including TNFRSF11A (RANK) and CSF1R for dysosteosclerosis, TONSL for SPONASTRIME dysplasia, EXTL3 for spondylo-epi-metaphyseal dysplasia with immune deficiency, and KIAA0753 for a novel type of skeletal ciliopathy.

Academic Significance and Societal Importance of the Research Achievements

早期発症の骨系統疾患の診断は、1) 十分な臨床症状を得るのが難しい、2) X線などの画像情報を得るのが難しい、3)骨格の成長・発達の個体差、年齢差が極めて大きい、ことなどから非常に困難である。多くの症例が、的確な診断が付かず、十分な治療が受けられない。一方で、早期発症骨系統疾患は、日常臨床の現場で、妊娠継続、延命処置の適否など重大な医学的決断を限られた時間内に下さないといけない状況におかれる場合が多い。迅速・簡便でかつ再現性のある診断方法の開発が喫緊の課題となっている。
早期発症の骨系統疾患の包括的遺伝子診断法の開発はこの課題を克服出来る。それには、原因遺伝子の同定が出発点となる。

Research Products

• [Journal Article] Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia (2019)
  • Author(s): Chang HR, Cho SY, Lee JH, Lee E, Seo J, Lee HR, Cavalcanti DP, Makitie O, Valta H, Girisha KM, Lee C, Neethukrishna K, Bhavani GS, Shukla A, Nampoothiri S, Phadke SR, Park MJ, Ikegawa S, Wang Z, (以下15名省略）, Cho TJ.
  • Journal Title: The American Journal of Human Genetics Volume: 104 Issue: 3 Pages: 439-453
  • DOI: 10.1016/j.ajhg.2019.01.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation (2019)
  • Author(s): Guo L, Bertola DR, Takanohashi A, Saito A, Segawa Y, Yokota T, Ishibashi S, Nishida Y, Yamamoto GL, Franco JFdS, Honjo RS, Kim CA, Musso CM, Timmons M, Pizzino A, Taft RJ, (以下21名省略）, Ikegawa S.
  • Journal Title: The American Journal of Human Genetics Volume: 104 Issue: 5 Pages: 925-935
  • DOI: 10.1016/j.ajhg.2019.03.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dysosteosclerosis is also caused by TNFRSF11A mutation. (2018)
  • Author(s): Guo L, Elcioglu NH, Karalar OK, Topkar MO, Wang Z, Sakamoto Y, Matsumoto N, Miyake N, Nishimura G, Ikegawa S#.
  • Journal Title: J Hum Genet. Volume: 63(6) Issue: 6 Pages: 769-774
  • DOI: 10.1038/s10038-018-0447-6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Further expansion of the mutational spectrum of spondylo-meta-epiphyseal dysplasia with abnormal calcification (2018)
  • Author(s): ?rel-Demir Gizem、Simsek-Kiper Pelin Ozlem、Akg?n-Do?an ?zlem、G??men Rah?an、Wang Zheng、Matsumoto Naomichi、Miyake Noriko、Utine G?len Eda、Nishimura Gen、Ikegawa Shiro、Boduroglu Koray
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 9 Pages: 1003-1007
  • DOI: 10.1038/s10038-018-0473-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies (2017)
  • Author(s): Hammarsjo A.、Wang Z.、（以下24名）
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15585-15585
  • DOI: 10.1038/s41598-017-15442-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia (2017)
  • Author(s): *Long Guo, *Nursel H Elcioglu, *Shuji Mizumoto, Zheng Wang, Bilge Noyan, Hatice M Albayrak, Shuhei Yamada, Naomichi Matsumoto, Noriko Miyake, Gen Nishimura, Shiro Ikegawa (equal contribution)
  • Journal Title: Journal of Human Genetics Volume: － Issue: 8 Pages: 797-801
  • DOI: 10.1038/jhg.2017.38
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations (2017)
  • Author(s): Wang Zheng、Horemuzova Eva、Iida Aritoshi、Guo Long、Liu Ying、Matsumoto Naomichi、Nishimura Gen、Nordgren Ann、Miyake Noriko、Tham Emma、Grigelioniene Giedre、Ikegawa Shiro
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 4 Pages: 503-506
  • DOI: 10.1038/jhg.2016.157
  • NAID: 40021158326
  • Peer Reviewed / Int'l Joint Research
• [Presentation] New Discovery on the Basic Research of Camurati-Engelmann Disease (2019)
  • Author(s): Wang Zheng
  • Organizer: 第9回 Orthopedic Research Club
  • Invited
• [Remarks] 理研IMS
  • URL: http://www.riken.jp/research/labs/ims/bone_joint_dis/
• [Remarks] 骨関節疾患研究チーム
  • URL: http://www.riken.jp/lab-www/OA-team/achieve.html