Genetic Analysis of Disheveled 2 and Disheveled 3 in Human Neural Tube DefectsReport as inadecuate

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Journal of Molecular Neuroscience

, Volume 49, Issue 3, pp 582–588

First Online: 15 August 2012Received: 26 June 2012Accepted: 31 July 2012


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.

KeywordsNeural tube defects NTDs Planar cell polarity PCP pathway Mouse models Disheveled Dvl Patrizia De Marco and Elisa Merello contribute equally to this work.

Electronic supplementary materialThe online version of this article doi:10.1007-s12031-012-9871-9 contains supplementary material, which is available to authorized users.

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Author: Patrizia De Marco - Elisa Merello - Alessandro Consales - Gianluca Piatelli - Armando Cama - Zoha Kibar - Valeria Capra


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