Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis

• DOI: 10.7554/elife.89762.4
• Publication Date: 2024-01-26T15:50:44Z
• Authors: Hao Yu; Anas M Khanshour; Aki Ushiki; Nao Otomo; Yoshinao Koike; Elisabet Einarsdo...; Yanhui Fan; Lilian Antunes; Yared H Kidane; Reuel Cornelia; Rory R Sheng; Yichi Zhang; Jimin Pei; Nick V Grishin; Bret M Evers; Jason Pui Yin Cheung; John A Herring; Chikashi Terao; You-qiang Song; Christina A Gurnett; Paul Gerdhem; Shiro Ikegawa; Jonathan J Rios; Nadav Ahituv; Carol A Wise
• Keywords: MMP3

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms drive AIS are largely unknown. We previously defined female-specific genetic locus an enhancer near PAX1 gene. Here, we sought define roles newly identified AIS-associated genes developmental mechanism AIS. In study 10,519 individuals 93,238 unaffected controls, significant association was variant COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E –11 , OR = 1.118). Using CRISPR mutagenesis generated Pax1 knockout mice ( -/ - ). postnatal spines found protein both localize within intervertebral disc-vertebral junction region encompassing growth plate, less detected -/- wild-type. By targeting wild-type Col11a1 expression costal chondrocytes suppresses Mmp3 matrix metalloproteinase 3 enzyme implicated remodeling. However, latter suppression abrogated presence P1335L mutant. Further, either knockdown estrogen receptor gene Esr2 or tamoxifen treatment significantly altered chondrocytes. propose new model pathogenesis wherein variation signaling increase susceptibility by altering PAX1-COL11a1-MMP3 axis