Deletion of a <i>Pax1</i> Sex-Associated Genomic Region Associated With Adolescent Idiopathic Scoliosis Leads to Disc Degeneration, Instability, and Vertebral Rotation in Mice.
basic_science · Level V
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- Record sourced from PubMed, PMID 42039795.
- Also identified by DOI 10.1002/jsp2.70177 and PMC identifier 13102530.
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Abstract
Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity characterized by three-dimensional curvature of the spine with an unknown etiology. Previous genome-wide association studies have identified a single-nucleotide polymorphism (rs6137473) located downstream of <i>PAX1,</i> which is significantly associated with female AIS risk. To investigate the role of this region in spinal development and AIS pathogenesis, we generated a mouse model with deletion of a nearby conserved sex-associated region (<i>Pax1</i>-SARΔ). Spines were examined by both micro-CT and histology. Gene expression analysis (by RNA-sequencing and quantitative PCR) was carried out on E12.5 and E18.5 developing spines. Glycosaminoglycan (GAG) content was also measured by high-performance liquid chromatography. Micro-CT analysis revealed increased vertebral rotation at T4 in female <i>Pax1</i>-SARΔ mice at 4 months and at T9 in male <i>Pax1</i>-SARΔ mice at 6 months, along with kyphotic and lordotic sagittal curvatures. Histological examination revealed significant intervertebral disc degeneration, with the most severe changes observed in the female <i>Pax1</i>-SARΔ mice. GAG analysis found decreased chondroitin sulfate and dermatan sulfate content in male and female <i>Pax1</i>-SARΔ mice. Gene expression analysis at E12.5 showed upregulation of <i>Pax1, Stat3, Ar</i>, <i>Foxa2,</i> and <i>Nkx2.2</i>, while RNA-sequencing at E18.5 revealed sex-dependent changes in gene expression related to extracellular matrix components, immune and inflammatory responses, and scoliosis. These findings highlight the pivotal role of the <i>Pax1</i> sex-associated genomic region in the development and maintenance of functional cartilage, extracellular matrix integrity, and intervertebral disc health, offering insights into the mechanisms underlying spinal degeneration and instability in AIS.