The genes involved in common serious birth defects such as neural tube closure defects (NTDs) are mostly unknown. Non-Mendelian recurrence risks suggest causation by oligogenic combinations of gene variants. Morphogenesis of the neural tube requires initial planar cell polarity (PCP)-based narrowing of the midline, across which the neural folds initiate contact and “zip together” bidirectionally to form the neural tube. Failure of the initial contact leads to an entirely open neural tube, craniorachischisis (CRN), which is very rare. More common is later failure at the ends of the “zipper”, which leads to anencephaly (cranial) or spina bifida (caudal). In mouse mutants, a wide variety of genes cause anencephaly and spina bifida, but only genes that affect PCP cause CRN.
In this issue, Robinson et al. (Hum Mutat 33:440–447, 2012) demonstrate the presence of potentially causative missense mutations in the PCP genes CELSR1 and SCRIB in 8 of the 36 cases of CRN evaluated. For mutations in 5 cases (4 CELSR1 and 1 SCRIB), an in vitro assay demonstrated defective trafficking of the mutant proteins to their normal location at the cell membrane in polarized cells.
Robinson et al. have demonstrated for the first time that genetic defects in the PCP pathway are involved in causation of human craniorachischisis, an important milestone on the road to understanding the complexity of the genetic basis of neural tube closure defects. Based on this genetic foothold, future studies of the role of PCP genes in CRN should extend to functional tests of other CELSR1 and SCRIB alleles, examination of other PCP genes to illuminate the degree of heterogeneity involved, and analysis of digenic and trigenic variant combinations, particularly those whose proteins are known to interact.