Protein tyrosine kinase 7 (Ptk7) was shown to cause a very severe form of NTDs called craniorachischisis in a mouse model and genetically interacts with a core PCP member Vangl2 where double heterozygotes suffer from spina bifida.
The planar cell polarity (PCP) genes CELSR1, CELSR2, VANGL1, and VANGL2 have been implicated in NTD; these genes have roles in neural tube closure and ependymal ciliary movement.
Here, we present the results of VANGL1 and VANGL2 mutational screening in a series of 53 NTD patients and 27 couples with a previous NTD affected pregnancy.
We also show that Lrp6(Skax26-Jus) genetically interacts with a PCP mutant (Vangl2(Lp)) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity.
Of interest are two arginine residues, R181 and R274, that are highly conserved in Vangl protein homologues and found to be independently mutated in VANGL1 (R181Q and R274Q) and VANGL2 (R177H and R270H) in human cases of NTDs.
Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway.
Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations.