Genetic analysis of disheveled 2 and disheveled 3 in human neural tube defects.
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.
Neurosurgery Department, G. Gaslini Institute, Genova, 16148, Italy.
Patrizia
P
De Marco
Elisa
E
Merello
Alessandro
A
Consales
Gianluca
G
Piatelli
Armando
A
Cama
Zoha
Z
Kibar
Valeria
V
Capra
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D019943:Amino Acid Substitution; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D018389:Codon, Nonsense; D000072261:Dishevelled Proteins; D005006:Ethnicity / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000235:genetics*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C454220:CELSR1 cadherin, human; D015820:Cadherins; D002352:Carrier Proteins; D018389:Codon, Nonsense; C000606581:DVL2 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; C000606585:Dvl3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C488287:VANGL1 protein, human; C468513:VANGL2 protein, human