TY - JOUR
T1 - Genetic Analysis of Disheveled 2 and Disheveled 3 in Human Neural Tube Defects
AU - De Marco, Patrizia
AU - Merello, Elisa
AU - Consales, Alessandro
AU - Piatelli, Gianluca
AU - Cama, Armando
AU - Kibar, Zoha
AU - Capra, Valeria
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Disheveled (Dvl)
KW - Mouse models
KW - Neural tube defects (NTDs)
KW - Planar cell polarity (PCP) pathway
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U2 - 10.1007/s12031-012-9871-9
DO - 10.1007/s12031-012-9871-9
M3 - Article
C2 - 22892949
AN - SCOPUS:84880330899
VL - 49
SP - 582
EP - 588
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
SN - 0895-8696
IS - 3
ER -