Adolescent idiopathic scoliosis (AIS) remains a challenging spinal deformity due to its complex genetic roots. Recent research highlights how ciliary Hedgehog signaling plays a pivotal role in maintaining the integrity of the intervertebral disc. Scientists have identified that two specific genes, Filamin B (FLNB) and TTC26, must work in synergy to preserve spinal stability. This discovery provides new insights into the molecular basis of gene-gene interactions in AIS development.

The Synergy of FLNB and TTC26

The study utilized mouse models to observe how combined genetic variations affect the spine. While single gene mutations caused only mild susceptibility, double heterozygous mice developed significant spinal curvature during puberty. This progression mirrors the clinical presentation of AIS in human adolescents. Furthermore, the research showed that these mutations lead to reduced production of collagen type II and aggrecan in the nucleus pulposus. In addition, the loss of these proteins was accompanied by a spike in matrix-degrading enzymes.

Impact of Ciliary Hedgehog Signaling on Spine Stability

At the molecular level, the simultaneous loss of FLNB and TTC26 suppresses Sonic hedgehog (Shh) signaling. TTC26 is essential for localizing protein arginine methyltransferase 7 (PRMT7) to the primary cilium. This localization enables the methylation of the transcription factor GLI2. Subsequently, FLNB binds to this methylated GLI2 to facilitate its entry into the nucleus. Without this mechanism, the intervertebral disc matrix begins to degrade rapidly because the Hh-GLI2 axis is compromised.

Consequently, the disruption of this ciliary Hedgehog signaling pathway leads to an increase in matrix-degrading enzymes. Restoring this pathway in vivo has shown potential in improving the extracellular matrix composition in mutant discs. These findings suggest that targeting Shh-GLI2 signaling could be a viable therapeutic strategy for managing spinal instability in adolescents. Moreover, identifying these genetic markers could lead to better screening for those at high risk of curve progression.

FAQs on AIS and Genetic Factors

What is the role of FLNB in scoliosis?

FLNB encodes a cytoskeletal protein that regulates primary cilia and matrix homeostasis. In the context of AIS, it helps transport critical transcription factors like GLI2 into the nucleus to maintain intervertebral disc health.

How does TTC26 contribute to spinal health?

TTC26 is involved in the transport of proteins within the primary cilium. It specifically helps move PRMT7, which is necessary for the biochemical activation of pathways that protect the intervertebral disc matrix from degradation.

Can restoring Shh signaling help patients with AIS?

While human clinical trials are pending, animal studies show that restoring Shh signaling improves the composition of the extracellular matrix. This suggests that future therapies targeting this pathway might stabilize the spine and slow scoliosis progression.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice or establish a doctor-patient relationship. Refer to the latest local and national guidelines for clinical practice.

References

Jiang H et al. FLNB and TTC26 regulate ciliary Hedgehog signaling to maintain intervertebral disc matrix homeostasis in adolescent idiopathic scoliosis. Genome Biol. 2026 May 25. doi: 10.1186/s13059-026-04107-w. PMID: 42178579.

Zhang L et al. Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms. PMC/NIH. 2024 Feb 3.

Juul TM et al. Severe Osteoporosis in Larsen Syndrome—A Case Report of Bone Morphology and A Novel Filamin B (FLNB) Variant. Calcified Tissue Int. 2025 Oct.