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Deletion of a Pax1 sex-associated genomic region associated with adolescent idiopathic scoliosis leads to disc degeneration, instability, and vertebral rotation in mice

ABSTRACT: Background 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 PAX1, which is significantly associated with female AIS risk. Methods 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 (Pax1-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. Results Micro-CT analysis revealed increased vertebral rotation at T4 in female Pax1-SARΔ mice at 4 months and at T9 in male Pax1-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 Pax1-SARΔ mice. GAG analysis found decreased chondroitin sulfate and dermatan sulfate content in male and female Pax1-SARΔ mice. Gene expression analysis at E12.5 showed upregulation of Pax1, Stat3, Ar, Foxa2, and Nkx2.2, while RNA-sequencing at E18.5 revealed sex-dependent changes in gene expression related to extracellular matrix components, immune and inflammatory responses, and scoliosis. Conclusion: These findings highlight the pivotal role of the Pax1 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE324970 | GEO | 2026/05/14

REPOSITORIES: GEO

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Project description:Adolescent Idiopathic Scoliosis (AIS) is the most common orthopedic condition requiring surgery, affecting 4% of adolescents. There is currently no proven method or prognostic test to identify symptomatic patients at risk of developing severe scoliosis who could benefit from growth-guided devices or minimally invasive non-fusion instrumentation surgeries. These innovative treatments must be performed at an early disease stage in younger patients to benefit from their growth potential. In this prospective cross-sectional study, we investigated the clinical utility of circulating microRNAs (miRNAs), an important class of small non-coding RNA, as biomarkers to predict the risk of developing severe scoliosis in AIS. Blood samples and clinical data were collected from 116 AIS patients who were followed until skeletal maturity and stratified according to their clinical outcome. Genome-wide expression profiling of miRNAs was performed with plasma obtained at the time of diagnosis of AIS (mean age of 13.3 ± 1.7 years with a mean Cobb angle of 24.4° ± 12.4°). This approach led to the identification of 15 circulating miRNAs that are upregulated in AIS patients who developed a severe scoliosis (Cobb angle ≥45°) at skeletal maturity compared to moderate and mild scoliosis groups (Cobb angle between 25°-44° and <25° respectively). After optimization and the application of Random Forest Models a panel of six miRNAs (miR-1-3p, miR-19a-3p, miR-19b-3p, miR-133b, miR-143-3p, and miR-148b-3p) out of 15 led us to develop an algorithm predicting the risk of developing a severe scoliosis with great accuracy (100%), sensitivity (100%) and specificity (100%). Having a scoliosis predictive bioassay and decision-making tools to predict curve progression in order to find the best treatment plan will undoubtedly transform the orthopedic care system in the field of pediatric scoliosis by integrating innovative precision medicine approaches. In addition, investigation of genes targeted by these miRNAs could fill our gaps in our understanding of AIS pathogenesis and reveal new actionable targets.

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Deletion of a Pax1 sex-associated genomic region associated with adolescent idiopathic scoliosis leads to disc degeneration, instability, and vertebral rotation in mice

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