Mutation of the Planar Cell Polarity Gene VANGL1 in Adolescent Idiopathic Scoliosis.

Study Design: Mutation analysis of a candidate disease gene in a cohort of patients with moderate to severe Adolescent idiopathic scoliosis (AIS).

Objective: To investigate if damaging mutations in the planar cell polarity gene VANGL1 could be identified in AIS patients.

Summary Of Background Data: AIS is a spinal deformity which occurs in 1% to 3% of the population. The cause of AIS is often unknown, but genetic factors are important in the etiology. Rare variants in genes encoding regulators of WNT/planar cell polarity (PCP) signaling were recently identified in AIS patients.

Methods: We analyzed the coding region of the VANGL1 gene for mutations using Sanger sequencing in 157 unrelated patients with moderate to severe AIS. The frequency of mutations in the patient cohort was compared with their frequency in a large cohort of controls. Functional effect of mutations were predicted in silico and analyzed in vitro by transfection of normal and mutant recombinant VANGL1 protein in Madin-Darby Canine Kidney (MDCK) cells. Cellular localization of recombinant proteins was analyzed by immunofluorescence microscopy analysis.

Results: In the patient cohort, we identified two rare missense mutations in VANGL1, encoding a receptor involved in WNT/PCP signaling. The mutations, p.I136N and p.F440 V, are very rare in the normal population. Both mutations are predicted to be damaging, and to affect evolutionary conserved amino acid residues of VANGL1. Functional analysis in MDCK cells showed that the mutations abolished the normal translocation of VANGL1 to the cell membrane.

Conclusion: Our data support that mutations in genes involved in WNT/PCP signaling may be associated with AIS, but replication in other patient cohorts and further analysis of the role of WNT/PCP signaling in AIS is needed.

Level Of Evidence: 4.