FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis.

backgroundAdolescent idiopathic scoliosis (AIS) is a complex spinal deformity with evidence of contributions from multiple genetic factors, but the molecular basis of gene-gene interactions in its development remains unclear. Filamin B (FLNB) and tetratricopeptide repeat domain 26 (TTC26) have both been implicated in the regulation of primary cilia and extracellular matrix homeostasis. However, whether combined variation in these genes contributes to spinal instability has not been established.

resultsWe generated mice carrying heterozygous mutations in both Flnb and Ttc26 and find that these double heterozygous mice develop progressive spinal curvature during puberty, whereas single gene mutants show only mild susceptibility. We observed reduced production of collagen type II and aggrecan in the intervertebral disc, accompanied by increased expression of matrix degrading enzymes. Transcriptomic and cellular analyses show that simultaneous loss of Flnb and Ttc26 suppresses Sonic hedgehog (Shh) signaling in the nucleus pulposus, due to impaired methylation and nuclear accumulation of the transcription factor GLI2. We find that TTC26 is required for the localization of protein arginine methyltransferase 7 (PRMT7) to the primary cilium, enabling methylation of GLI2, while FLNB binds methylated GLI2 to promote its nuclear import. Restoring Shh signaling in vivo improves extracellular matrix composition in mutant discs.

conclusionsThese findings show that FLNB and TTC26 act together to regulate Shh-GLI2 signaling and maintain extracellular matrix homeostasis in the intervertebral disc. Their combined disruption compromises spine stability and may contribute to the pathogenesis of adolescent idiopathic scoliosis.