Neural tube defects (NTDs) originate during mammalian embryogenesis when the neural folds fail to fuse at the midline, where they should form into a closed tube. NTDs are the second most common type of birth defect, and can lead to conditions including spina bifida and anencephaly. This report describes a model of neural tube defects caused by variants in VANGL1 and VANGL2, which show autosomal dominant inheritance. There is a single high-ranking ortholog of VANGL1 and VANGL2 in Drosophila, Vang, for which classical loss-of-function alleles, alleles carrying RNAi targeting constructs, and more have been generated.
Neither of the human genes VANGL1 nor VANGL2 have been introduced into flies.
Overexpression of Vang in the wing causes hair reorientation defects distinct from those seen in Vang-null flies, which is indicative of incorrect cell polarity determination. Fly Vang alleles modified to model six patient-derived variants show changes in intracellular localization and binding to effectors including dsh and pk, covering a spectrum from loss-of-function to dominant negative gain-of-function mutant alelles.
[updated May 2020 by FlyBase; FBrf0222196]
[NEURAL TUBE DEFECTS, SUSCEPTIBILITY TO; NTD](https://omim.org/entry/182940)
[VANGL PLANAR CELL POLARITY PROTEIN 1; VANGL1](https://omim.org/entry/610132)
[VANGL PLANAR CELL POLARITY PROTEIN 2; VANGL2](https://omim.org/entry/600533)
[T-BOX TRANSCRIPTION FACTOR T; TBXT](https://omim.org/entry/601397)
[CHEMOKINE, CC MOTIF, LIGAND 2; CCL2](https://omim.org/entry/158105)
[FUZZY PLANAR CELL POLARITY PROTEIN; FUZ](https://omim.org/entry/610622)
By direct sequencing of the VANGL1 gene, Merello et al. 2015 (pubmed:25208524) identified 3 heterozygous missense variants (A187V, D389H, and R517H) that were not present in 200 matched Italian controls. The variants were found in a girl with lipomyeloschisis, an unaffected woman who had a pregnancy complicated by anencephaly, and a boy with myelomeningocele, respectively. Two additional synonymous variants were found in a child with cephalocele and in the father of a fetus with myelomeningocele. [Adapted from MIM:182940, 2020.05.11]
In 3 (2.1%) of 144 unrelated patients with various forms of neural tube defects from Slovakia, Romania, and Germany who underwent direct sequencing of the VANGL1 gene, Bartsch et al. 2012 (pubmed:23326252) identified 3 different heterozygous missense variants (R173H, R186H, and G25R). The patients had sporadic neural tube defects, sporadic spinal lipoma and tethered cord, and sporadic lumbosacral meningomyelocele, respectively.
Although the unifying feature of open neural tube disorders (NTDs) is incomplete neural tube closure, evidence points to many different possible causes, both genetic and environmental. In humans, it appears that most NTDs are multifactorial, resulting from an additive contribution of several risk factors, which are each individually insufficient to disrupt neural tube closure (the multifactorial threshold model). The challenge of identifying the primary cause of NTDs in individual patients is highlighted by the numerous candidate genes and environmental factors indicated by epidemiologic studies and experimental models. Moreover, the potential for gene-gene and gene-environment interactions introduces further potential complexity. (From Greene and Copp 2014 and references therein, pubmed:25032496.)
Neural tube defects represent a complex trait with multifactorial etiology encompassing both genetic and environmental components (summary by Bartsch et al. 2012, pubmed:23326252; and Lei et al. 2014, pubmed:24632739). [from MIM:182940, 2020.05.11]
The mammalian core PCP (planar cell polarity) genes Vangl1/2, and Vang in Drosophila, play essential roles in planar polarity signaling. Vang interacts genetically with each PCP core gene. It has further been demonstrated that it also can physically interact with all other members of the PCP complex, and the interaction sites with the cytoplasmic PCP core factors have been mapped to its C-terminal domain. While mutations have been observed along the entire span of the VANGL1/2 genes in human NTD patients, mutations known to be causative for NTD in the mouse all map to the C-terminal tail. (From Humphries et al. 2020 and references therein, FBrf0245453.)
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
Single, high-scoring ortholog of both human paralogs VANGL1 and VANGL2.
