24Common bone and joint diseases are serious worldwide problems for health and the economy, as exemplified by the WHO initiative “Bone and Joint De-cade” (2000-2010) and the “Locomotive syndrome campaign” in Japan. We are searching for susceptibility genes for common (polygenic) bone and joint diseases, including osteoarthritis (OA), lumbar disc disease (LDD)/herniation (LDH), osteoporosis, avascular necrosis of the femoral head (ANF), scoliosis, and ossification of the posterior longitudinal ligament of the spine (OPLL).Through genome-wide association studies (GWASs) and next-generation sequencing approaches, we identify and characterize susceptibility genes and clarify their disease-causing mechanisms at the molecular level. Using the ge-nome information obtained from these studies, we will realize our final goal of “personalized medicine”. GWASs for OA, LDD/LDH, adolescent idiopathic sco-liosis, OPLL, and ANF are in progress and we have succeeded in the identifica-tion of many susceptibility genes. Functional studies of the genes in vitro and using animal models are underway.2) Genomic Study of Skeletal DysplasiaSkeletal dysplasia is a group of heritable (monogenic) disorders affecting the skeleton, and more than 450 diseases belong to this category. Skeletal dysplasia is an intractable disease, so many patients are waiting for an effective treatment. We are engaged in clinical and basic studies of these difficult diseases. By large-scale mutation screening, including exome sequencing, we are identifying the disease-causative genes. By now, we have identified 30 novel genes including TMEM53 for craniotubular dysplasia, Ikegawa type, and SLC4A2 for osteope-trosis, Ikegawa type.Through the analyses of phenotypes and diseases genes, we seek to under-stand the molecular mechanisms of bone and joint formation and the patho-genesis of common bone and joint diseases, as well as to contribute to the diagnosis and treatment of rare intractable diseases. Using the disease genes for skeletal dysplasia as candidate genes, we perform association studies for com-mon bone and joint diseases corresponding to skeletal dysplasia, the so-called “rare to common” approach.Figure: Clinical features of craniotubular dysplasia, Ikegawa type, caused by bi-allelic loss of function mutations in TMEM53. The patients have dysplasias of the spine and the long and short tubular bones.Recent Major PublicationsGuo L, Iida A, Bhavani GS, Gowrishankar K, Wang Z, Xue JY, Wang J, Miyake N, Matsumoto N, Hasegawa T, Iizuka Y, Matsuda M, Nakashima T, Takechi M, Iseki S, Yambe S, Nishimura G, Koseki H, Shukunami C, Girisha KM, Ikegawa S. Deficiency of TMEM53 causes a previously unknown sclerosing bone disorder by dysregulation of BMP-SMAD signaling. Nat Commun 6, 2046 (2021)Boer CG, Hatzikotoulas K, Southam L, Stefánsdóttir L, Zhang Y, Coutinho de Almeida R, Wu TT, Zheng J, .., Cheah KSE, Ikegawa S, Hveem K, Esko T, Wilkinson JM, Meulenbelt I, Lee MTM, van Meurs JBJ, Styrkársdóttir U, Zeggini E. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell 184, 4784-4818 (2021)Xue JY, Grigelioniene G, Wang Z, Nishimura G, Iida A, Matsumoto N, Tham E, Miyake N, Ikegawa S, Guo L. SLC4A2 deficiency causes a new type of osteopetrosis. J Bone Miner Res 37, 226-235 (2021)Invited presentationsIkegawa S. “Skeletal Dysplasia from the Basics” The 32nd Annual Meeting of the Japan Pediatric Orthopedic Soci-ety (Okayama, Japan/Online) December 2021Ikegawa S. “Genomic Study of Bone and Joint Diseases–present and future” The 36th Annual Meeting of the Japan Orthopedic Society Basic Research Meeting (Tokyo, Japan/Online) October 2021Ikegawa S. “Progress in skeletal dysplasia diagnosis and experience in Japan” The Asia-Pacific Skeletal Dysplasia Meeting (Hong Kong/Online) May 2021Ikegawa S. “Genomic Study of Rare Diseases of Skeleton” APAC MPS Summit 2021 (Taipei/Online) May 2021Laboratory for Bone and Joint DiseasesTeam Leader: Shiro Ikegawa1) Genomic Study of Common Diseases
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