Abstract
Craniorachischisis is a severe neural tube defect (NTD) resulting from failure to initiate closure, leaving the hindbrain and spinal neural tube entirely open. Clues to the genetic basis of this condition come from several mouse models, which harbour mutations in core members of the planar cell polarity (PCP) signalling pathway. Previous studies of humans with craniorachischisis failed to identify mutations in the core PCP genes
VANGL1
and
VANGL2
. Here we analysed other key PCP genes:
CELSR1
,
PRICKLE1
,
PTK7
and
SCRIB,
with the finding of eight potentially causative mutations in both
CELSR1
and
SCRIB.
Functional effects of these unique or rare human variants were evaluated using known protein-protein interactions as well as subcellular protein localisation. While protein interactions were not affected, variants from 5 of the 36 patients exhibited a profound alteration in subcellular protein localisation, with diminution or abolition of trafficking to the plasma membrane. Comparable effects were seen in the
crash
and
spin cycle
mouse
Celsr1
mutants, and the
line-90
mouse
Scrib
mutant. We conclude that missense variants in
CELSR1
and
SCRIB
may represent a cause of craniorachischisis in humans, as in mice, with defective PCP protein trafficking to the plasma membrane a likely pathogenic mechanism.