Mutations in the planar cell polarity genesCELSR1andSCRIBare associated with the severe neural tube defect craniorachischisis

Abstract

Craniorachischisis (CRN) 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 harbor mutations in core members of the planar cell polarity (PCP) signaling pathway. Previous studies of humans with CRN failed to identify mutations in the core PCP genes, VANGL1 and VANGL2. Here, we analyzed 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 proteinprotein interactions as well as subcellular protein localization. While protein interactions were not affected, variants from five of the 36 patients exhibited a profound alteration in subcellular protein localization, 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 CRN in humans, as in mice, with defective PCP protein trafficking to the plasma membrane a likely pathogenic mechanism.

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

“…We and others have previously demonstrated an important role for PCP signaling in the pathogenesis of NTDs where novel and rare mutations in PCP genes including VANGL1, PK1, FZD6, FUZZY, SCRIBBLE1 and CELSR1 were associated with NTDs in a subset of patients (37)(38)(39)(40)(41)(42). All these genes are activators of the PCP pathway, and some mutations were hypothesized to be hypomorphic.…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…Mutations in ADGRC1 (CELSR1) cause neural tube defects as well as caudal agenesis in humans (Allache et al, 2012;Robinson et al, 2012). Similarly, mice with missense mutations in Adgrc1 (Celsr1) show craniorachischisis, a severe neural tube defect (Curtin et al, 2003).…”

Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes

“…Each of these anomalies appears to have complex genetic and environmental influences (Dixon et al, 2011;Au et al, 2010;Wessels and Willems, 2010;Grosen et al, 2011). For rare patients with neural tube defects, a connection to PCP signaling comes from the finding of VANGL1, CELSR1, SCRIB and FUZ (the latter two are homologs of the Drosophila PCP genes scribbled and fuzzy, respectively) sequence variants (Kibar et al, 2007;Kibar et al, 2009;Kibar et al, 2011;Seo et al, 2011;Robinson et al, 2012). For human palate closure defects, there are statistically significant associations with single-nucleotide polymorphisms in the WNT3, WNT3A, WNT5A, WNT8A and WNT11 genes (Chiquet et al, 2008;Menezes et al, 2010;Yao et al, 2011;Mostowska et al, 2012).…”