Genetic studies of ANKRD6 as a molecular switch between Wnt signaling pathways in human neural tube defects

Planar cell polarity (PCP) is a major branch of Wnt signaling that controls the process of convergent extension in gastrulation and neurulation. PCP defects were associated with neural tube defects (NTDs) that are the most common central nervous system anomalies. PCP signaling is highly dosage sensitive and exhibits an antagonistic relationship with the canonical Wnt/β-catenin pathway. Diversin, encoded by Ankrd6, is an ankyrin repeat protein that activates the non canonical PCP signaling and simultaneously inhibits the canonical pathway.

In this study, we analyzed this dual role of ANKRD6 in NTDs. We sequenced its coding region in 473 NTD patients and 150 controls, and we validated the effect of the identified variants on Wnt signaling using reporter assays in mammalian cells.

We identified four rare missense mutations in 0.8% of the NTD patients and two rare missense mutations in 1.3% of the controls. Notably, when all six mutations were validated, only two mutations identified in NTD patients, p.Pro548Leu, p.Arg632His, significantly altered DIVERSIN activity in Wnt signaling assays in a hypomorphic manner.

Rare missense mutations in ANKRD6 could affect a balanced reciprocal antagonism between both Wnt pathways in neurulation and act as predisposing factors to NTDs in a subset of patients.