Vangl1+Mutations


 * Mutations in //VANGL 1// and Neural Tube Defects **

Researchers from McGill University and the University of Montreal and studied the effects of mutations in the human //VANGL//1gene. The study was conducted on 144 patients with neural tube defects,and a control group consisting of 106 patients with unrelated problems. The team amplified the coding exons of //VANGL1// (NCBI NM_138959) and the physical interactions of human //VANGL1// and disheveled proteins were documented. They identified three patients that were heterozygous for missense mutations in //VANGL1//, V239I, R274Q, M328T. All three mutations were determined to affect amino acid residues conserved in //VANGL// family(1). Eight other sequence variants in ORF were silent and did not change the predicted amino acid. //VANGL2// was sequenced and several variants were found but none were predicted to affect protein sequence (1).



 The mutation V239I, substitution of valine with isoleucine at position 239, is located on fourth predicted transmembrane protein and is conserved across all known Vangl proteins. The substitution of isoleucine preserves the hydrophobicity of valine but produces a bulky side chain that renders a non functional or altered protein. V239I stops the interaction of VANGL with Dvl proteins which interferes with Dvl in the plasma membrane and changes signaling during neural tube development and closure. This mutation interacts with other genetic loci and other unknown environmental factors to produce different degrees of severity in the defect (1). Mutation R274Q is a missense mutation, substituting glutamine for arginine at position 274, located in the cytoplasmic domain. It is invariant in all known orthologs except C. elegans in which glutamine is substituted for glutamate preserving the charged character of arginine. The substituted glutamine does not preserve this charged character. Defects were varied and familial in some patients (1). Mutation M328T, substitutes methionine with threonine at position 328 in the cytoplasmic domain of VANGL1. Methionine has a hydrophobic character that is conserved across evolutionary domains. M328T is not conserved because threonine contains a hydroxyl sidechain that increases hydrophobicity at this position. This mutation is associated with Chiari II malformation and lumbosacral scoliosis (1).



Previously it was established that //VANGL// genes interact with //Dishevelled// genes in the PCP pathway. The mutant variants V239I, R274Q, and M238T were all tested for their ability to interact with //DVL// genes by yeast two hybrid systems. The V239I mutation completely inhibited interaction with all three //Dvl// proteins.The R274Q and M328T mutations had no effect on the //Dvl// interaction in the assay(1). The results of this research confirm the crucial role of //VANGL// and //Dvl// genes in the planar cell polarity cascade of neural tube development. The study was inconclusive on the heritability of these mutations and V239I was determined to be a //de novo// mutation, a new mutation that occurs in a germ cell and is passed down to offspring (2). The three studied mutations affect residues conserved in //Vangl// proteins across species and changed the planar cell polarity pathway resulting in various neural tube disorders. The interaction of V239I with //Dvl// proteins was established, and agrees with the multifactoral model for neural tube defects.

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 1.Kibar Ph.D., Zoha, et al. “Mutations in VANGL1 Associated with Neural - Tube Defects.” New England Journal of Medicine 356 (Apr. 2007): 1432- 1437. Print. 2.Kibar, Zoha, et al. “Novel Mutations in VANGL1 in Neural Tube Defects.” Human Mutations 30(7) (July 2009): E706-E715. Print.