Identification of a functional susceptibility variant for adolescent idiopathic scoliosis that upregulates early growth response 1 (EGR1)-mediated <em>UNCX</em> expression

Yonezawa, Yoshiro; Guo, Long; Kakinuma, Hisaya; Otomo, Nao; Yoshino, Soichiro; Takeda, Kazuki; Nakajima, Masahiro; Shiraki, Toshiyuki; Ogura, Yoji; Takahashi, Yohei; Koike, Yoshinao; Minami, Shohei; Uno, Koki; Kawakami, Noriaki; Ito, Manabu; Yonezawa, Ikuho; Watanabe, Kei; Kaito, Takashi; Yanagida, Haruhisa; Taneichi, Hiroshi; Harimaya, Katsumi; Taniguchi, Yuki; Shigematsu, Hideki; Iida, Takahiro; Demura, Satoru; Sugawara, Ryo; Fujita, Nobuyuki; Yagi, Mitsuru; Okada, Eijiro; Hosogane, Naobumi; Kono, Katsuki; Chiba, Kazuhiro; Kotani, Toshiaki; Sakuma, Tsuyoshi; Akazawa, Tsutomu; Suzuki, Teppei; Nishida, Kotaro; Kakutani, Kenichiro; Tsuji, Taichi; Sudo, Hideki; Iwata, Akira; Sato, Tatsuya; Inami, Satoshi; Nakamura, Masaya; Matsumoto, Morio; Terao, Chikashi; Watanabe, Kota; Okamoto, Hitoshi; Ikegawa, Shiro

Affiliations

¹Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan

²Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan

³Department of Laboratory Animal Science, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China

⁴Laboratory for Neural Circuit Dynamics of Decision Making, RIKEN Brain Science Institute, Saitama, Japan

⁵Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

⁶Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

⁷Department of Orthopedic Surgery, Graduate School of Medical Sciences, Hokkaido University, Sapporo, Japan

⁸Department of Orthopedic Surgery, Seirei Sakura Citizen Hospital, Chiba, Japan

⁹Department of Orthopedic Surgery, National Hospital Organization, Kobe Medical Center, Kobe, Japan

¹⁰Department of Orthopedic Surgery, Meijo Hospital, Nagoya, Japan

¹¹Department of Orthopedic Surgery, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan

¹²Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan

¹³Department of Orthopedic Surgery, Niigata University Medical and Dental General Hospital, Niigata, Japan

¹⁴Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan

¹⁵Department of Orthopedic Surgery, Fukuoka Children’s Hospital, Fukuoka, Japan

¹⁶Department of Orthopedic Surgery, Dokkyo Medical University School of Medicine, Tochigi, Japan

¹⁷Department of Orthopedic Surgery, Kyushu University Beppu Hospital, Beppu, Japan

¹⁸Department of Orthopedic, Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

¹⁹Department of Orthopedic Surgery, Nara Medical University, Nara, Japan

²⁰Department of Orthopedic Surgery, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan

²¹Department of Orthopedic Surgery, Kanazawa University Hospital, Kanazawa, Japan

²²Department of Orthopedic Surgery, Jichi Medical University, Tochigi, Japan

²³Department of Orthopedic Surgery, Fujita Health University, Nagoya, Japan

²⁴Department of Orthopedic Surgery, Kyorin University School of Medicine, Tokyo, Japan

²⁵Department of Orthopedic Surgery, Kono Orthopaedic Clinic, Tokyo, Japan

²⁶Department of Orthopedic Surgery, National Defense Medical College, Saitama, Japan

²⁷Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan

²⁸Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, Japan

²⁹Department of Preventive and Therapeutic Research for Metastatic Bone Tumor, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

Abstract and keywords

Adolescent idiopathic scoliosis (AIS) is a serious health problem affecting 3% of live births all over the world. Many loci associated with AIS have been identified by previous genome wide association studies, but their biological implication remains mostly unclear. In this study, we evaluated the AIS-associated variants in the 7p22.3 locus by combining in silico, in vitro, and in vivo analyses. rs78148157 was located in an enhancer of UNCX, a homeobox gene and its risk allele upregulated the UNCX expression. A transcription factor, early growth response 1 (EGR1), transactivated the rs78148157-located enhancer and showed a higher binding affinity for the risk allele of rs78148157. Furthermore, zebrafish larvae with UNCX messenger RNA (mRNA) injection developed body curvature and defective neurogenesis in a dose-dependent manner. rs78148157 confers the genetic susceptibility to AIS by enhancing the EGR1-regulated UNCX expression.

Keywords: GENETIC ANIMAL MODELS; CELL/TISSUE SIGNALING-TRANSCRIPTION FACTORS; DISEASES AND DISORDERS OF/RELATED TO BONE; HUMAN ASSOCIATION STUDIES; GENETIC RESEARCH

Links

DOI: 10.1002/jbmr.4738

PubMed: 36342191

WoS: 000890072100001

History

Received: 2022-07-22

Revised: 2022-10-23

Accepted: 2022-11-03