Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects
Patrizia De Marco1, Elisa Merello, Alessandro Consales
1Neurosurgery Department, G. Gaslini Institute, Genova, 16148, Italy.
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.
Insights
Rare variants in the DVL2 gene may increase the risk of neural tube defects (NTDs). This study identified several mutations in DVL2 in patients with NTDs, suggesting a potential role in disease development.
Area of Science:
- Developmental Biology
- Genetics
- Medical Research
Background:
- Neural tube defects (NTDs) are severe congenital malformations affecting approximately 1 in 1,000 live births.
- The planar cell polarity (PCP) pathway is crucial for neural tube closure, and its disruption is linked to NTDs in various models and human studies.
- Disheveled (DVL) proteins, particularly DVL2 and DVL3, are key regulators in both canonical Wnt signaling and noncanonical PCP pathways, playing a role in embryonic development.
Purpose of the Study:
- To investigate the role of human orthologs DVL2 and DVL3 in the pathogenesis of neural tube defects.
- To identify rare genetic variants in DVL2 and DVL3 in a cohort of patients with NTDs and compare them to ethnically matched controls.
Main Methods:
- Genotyping of rare variants in the DVL2 and DVL3 genes in 473 patients with NTDs.
- Comparison of identified variants with 639 ethnically matched controls.
- In silico prediction of the pathogenicity of identified mutations.
Main Results:
- Seven rare missense mutations in DVL2 and DVL3 were identified in the patient cohort, none of which were found in the control group.
- Two DVL2 mutations (p.Tyr667Cys and p.Ala53Val) were predicted to be detrimental.
- A 1-bp insertion in DVL2 (c.1801_1802insG), predicted to cause protein truncation, was found in a patient with caudal agenesis.
Conclusions:
- Rare variants in the DVL2 gene may represent a risk factor for neural tube defects.
- The findings suggest a potential role for DVL2 in human neural tube closure and NTD pathogenesis.
- Further research is warranted to fully elucidate the contribution of DVL2 variants to NTDs.
