Association of genetic variation in
Hao Yu1, Anas M Khanshour1, Aki Ushiki2,3
1Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX, USA.
Biorxiv : the Preprint Server for Biology
|June 9, 2023
Summary
Adolescent idiopathic scoliosis (AIS) is a spinal deformity more common in girls. This study identifies a new molecular pathway involving PAX1, COL11A1, and estrogen signaling that may explain disease development.
Area of Science:
- Genetics
- Developmental Biology
- Biochemistry
Background:
- Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with unknown molecular causes and a significant female predominance.
- Previous research identified a female-specific genetic risk locus near the PAX1 gene.
Approach:
- A large genetic study identified a novel association between AIS and a COL11A1 variant (rs3753841).
- CRISPR technology was used to create Pax1 knockout mice to study gene function in vivo.
- Experiments in chondrocytes investigated the interplay between COL11A1, PAX1, Mmp3, and estrogen signaling.
Key Points:
- A COL11A1 variant (rs3753841) is significantly associated with AIS risk.
- PAX1 and collagen (α1) XI proteins are localized in the growth plate region of the spine.
- Wildtype COL11A1 suppresses PAX1 and MMP3 expression in chondrocytes, but this is disrupted by the AIS-associated COL11A1 mutant.
- Estrogen receptor signaling influences COL11A1 and MMP3 expression.
Conclusions:
- A novel molecular model for AIS pathogenesis is proposed, involving a PAX1-COL11A1-MMP3 signaling axis.
- Genetic variations and estrogen signaling likely contribute to AIS susceptibility by disrupting this axis in spinal chondrocytes.
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