Association of genetic variation in <i>COL11A1</i> with adolescent idiopathic scoliosis.

Abstract

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