Identification of a Functional Susceptibility Variant for Adolescent Idiopathic Scoliosis that Upregulates Early Growth Response 1 (EGR1)-Mediated UNCX Expression

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)144-153
Number of pages10
JournalJournal of Bone and Mineral Research
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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