Genetic Analysis of Disheveled 2 and Disheveled 3 in Human Neural Tube Defects

Abstract

Neural tube defects are severe malformations affecting 1/1,000 live births. The planar cell polarity pathway controls the neural tube closure and has been implicated in the pathogenesis of neural tube defects both in animal models and human cohorts. In mouse disruption of Dvl2 alone (Dvl2−/−) or Dvl2 and Dvl3 (Dvl2−/−; Dvl3+/−, Dvl2+/−; Dvl3−/−) results in incomplete neurulation, suggesting a role for Disheveled in neural tube closure. Disheveled is a multifunctional protein that is involved in both the canonical Wnt signaling and the noncanonical planar cell polarity pathway. In this study, we analyzed the role of the human orthologs DVL2 and DVL3 in a cohort of 473 patients with neural tube defects. Rare variants were genotyped in 639 ethnically matched controls. We identified seven rare missense mutations that were absent in all controls analyzed. Two of these mutations, p.Tyr667Cys and p.Ala53Val, identified in DVL2 were predicted to be detrimental in silico. Significantly, a 1-bp insertion (c.1801_1802insG) in exon 15 of DVL2 predicted to lead to the truncation of the protein was identified in a patient with a complex form of caudal agenesis. In summary, we demonstrate a possible role for rare variants in DVL2 gene as risk factors for neural tube defects.Electronic supplementary materialThe online version of this article (doi:10.1007/s12031-012-9871-9) contains supplementary material, which is available to authorized users.

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…Mice with genetic disruptions in critical modulators of Wnt/PCP signaling, including Dact1 (Dapper, Frodo), Scribble (Scrib), cadherin EGF LAG seven-pass G-type receptor 1 (Celsr1), Dvl2, Vangl1, and Vangl2, have highly penetrant NTD phenotypes [40,41,42,43,44]. Importantly, human genomic studies of patients with NTDs have also revealed mutations in several of these same Wnt/PCP pathway genes [45,46,47,48,49,50,51,52]. A role for the Wnt/β-catenin pathway is indicated in this process as well.…”

Rare missense variants in DVL1, one of the human counterparts of the Drosophila dishevelled gene, do not confer increased risk for neural tube defects

“…The cohort used in this study was previously screened for mutations in DVL2 and DVL3 (De Marco et al, 2013). According to a model of interaction among loci, we searched for individuals who were carriers of two or more variants in the three human DVLs homologues, but no patients or controls with multiple heterozygosity was identified.…”

“…Dvls contain three highly conserved binding domains: an N-terminal DIX (Dishevelled and Axin) domain; a central PDZ (PSD-95, discs-large and ZO-1) domain; and a DEP domain (Wong et al 2000(Wong et al , 2003Capelluto et al, 2002 (Lijam et al, 1997;Wang et al, 2006). Very recently, we analyzed the role of the human orthologs DVL2 and DVL3 in a cohort of 473 patients affected with various forms of NTDs, and we could demonstrate a possible role for rare nonsynonymous variants in the DVL2 gene as risk factors for NTDs (De Marco et al, 2013). Now, we report the results of the resequencing of DVL1 on the same cohort of patients.…”

“…However, Dvl1 2/2 ; Dvl2 2/2 double mutants displayed craniorachishisis, a completely open neural tube from the midbrain to the tail (Lijam et al, 1997;Wang et al, 2006). Very recently, we analyzed the role of the human orthologs DVL2 and DVL3 in a cohort of 473 patients affected with various forms of NTDs, and we could demonstrate a possible role for rare nonsynonymous variants in the DVL2 gene as risk factors for NTDs (De Marco et al, 2013). Now, we report the results of the resequencing of DVL1 on the same cohort of patients.…”

Estrogen regulation of Dkk1 and Wnt/β-Catenin signaling in neurodegenerative disease

“…The canonical Wnt signaling pathway has since been deemed critical for several embryonic events, including cell proliferation, cell polarity, and determination of cell fate (Logan and Nusse, 2004; MacDonald et al, 2009). Canonical Wnt/β-Catenin signaling has also been implicated in development of the limbs (Grotewold and Ruther, 2002; Mukhopadhyay et al, 2001), neural tube (De Marco et al, 2012; Roelink and Nusse, 1991), forebrain (Mukhopadhyay et al, 2001), midbrain and cerebellum (McMahon and Bradley, 1990; Thomas and Capecchi, 1990) and in the maintenance of neurotransmission and synaptic plasticity (Ataman et al, 2008; Avila et al, 2010; Budnik and Salinas, 2011; Jensen et al, 2012; Speese and Budnik, 2007). In light of this knowledge, it is not surprising that, in addition to tumorigenesis, mutations that enhance Wnt signaling in humans have been linked to neurological disorders, such as autism, schizophrenia, and bipolar disorder (De Ferrari and Moon, 2006).…”