Alternative titles; symbols
HGNC Approved Gene Symbol: VANGL2
Cytogenetic location: 1q23.2 Genomic coordinates (GRCh38): 1:160,400,564-160,428,670 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q23.2 | Neural tube defects | 182940 | Autosomal dominant | 3 |
Planar cell polarity (PCP) is the term given to global cell polarization, such as the alignment of mammalian body hair along the anterior-posterior axis or the orientation of stereocilia bundles in the inner ear. VANGL2 is a PCP protein that is involved in the transmission of directional cues to align either individual cells within an epithelial sheet or multicellular clusters, which polarize as a group (Devenport and Fuchs, 2008).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1999) cloned VANGL2, which they designated KIAA1215. RT-PCR ELISA detected moderate expression in brain, lung, ovary, fetal brain, and all specific adult brain regions examined. Weak expression was detected in heart, skeletal muscle, kidney, pancreas, testis, and fetal liver, and no expression was detected in liver and spleen.
'Loop-tail' (Lp) is a semidominant mouse mutation that, in homozygous mutants, causes a severe form of neural tube defect called craniorachischisis. Heterozygous mice exhibit a characteristic looped tail, and homozygous embryos show a completely open neural tube in the hindbrain and spinal region. By an in silico search, Kibar et al. (2001) identified a mouse EST within the Lp interval homologous to a partial human cDNA clone, KIAA1215. Based on its relationship to the mouse disorder, Kibar et al. (2001) used the temporary designation 'loop-tail-associated protein' (Ltap). The Ltap gene encodes a homolog of Drosophila 'strabismus/Van Gogh' (Stbm/Vang), a component of the frizzled-dishevelled tissue polarity pathway. Ltap is expressed broadly in the neuroectoderm throughout early neurogenesis. This and the fact that the gene was altered in 2 independent Lp alleles identified it as the likely basis for loop-tail. The authors suggested that the human Ltap homolog is worthy of search for mutations that may be associated with sporadic or familial cases of neural tube defects in humans.
Murdoch et al. (2001) independently cloned the causative gene for craniorachischisis in Lp mice, which they named Lpp1. A single-base transition, 1841G-A, resulted in a ser464-to-asn (S464N) substitution. Lpp1 is expressed in the ventral part of the developing neural tube, but is excluded from the floorplate where Sonic hedgehog (Shh; 600725) is expressed. Embryos lacking Shh express Lpp1 throughout the ventral neural tube, suggesting negative regulation of Lpp1 by Shh. The authors suggested that the mutual interaction between Lpp1 and Shh may define the lateral boundary of floorplate differentiation. They hypothesized that loss of Lpp1 function may disrupt neurulation by permitting more extensive floorplate induction by Shh, thereby inhibiting midline bending of the neural plate during initiation of neurulation. The human ortholog of Lpp1, which maps to chromosome 1, shares 89% identity with the mouse gene at the nucleotide level and 99% identity at the amino acid level. Both mouse and human LPP1 proteins contain 521 amino acids. LPP1 has 4 predicted transmembrane regions, followed by a coiled-coil domain and a C-terminal PDZ-binding domain. Both the N and C termini were predicted to be cytoplasmic.
Park and Moon (2002) cloned the VANGL2 homolog stbm from zebrafish and Xenopus, using degenerate PCR primers. Zebrafish stbm shares 41%, 75%, 61%, and 76% amino acid identity with Drosophila, Xenopus, mouse, and human orthologs, respectively. Sequence analysis predicted 4 potential transmembrane domains close to the N terminus and a putative PDZ domain-binding motif at the C terminus.
Murdoch et al. (2001) determined that the VANGL2 gene contains 8 exons.
By radiation hybrid analysis, Nagase et al. (1999) mapped the VANGL2 gene to chromosome 1.
By linkage analysis, Stanier et al. (1995) mapped the mouse loop-tail mutation to a region of chromosome 1 that shows conserved homology with human chromosome 1q21-q23. Mullick et al. (1995) mapped the gene to the same region of mouse chromosome 1.
The region surrounding the mouse Lp locus, syntenic to human chromosome 1q21-q25, is significant in having been duplicated several times during the evolution of mammalian chromosomes, giving rise to clusters of paralogous genes. Doudney et al. (2001) constructed comparative physical and transcript maps of approximately 1 Mb around 'loop-tail.'
Park and Moon (2002) investigated the expression, functions, and signaling activities of the VANGL2 homolog stbm in zebrafish and Xenopus embryos. RT-PCR and in situ hybridization detected stbm expression throughout embryogenesis, enriched in the nervous system and peaking during the neurula stage in both species. Gain-of-function and loss-of-function experiments in zebrafish embryos showed that stbm modulates the morphogenetic movements of gastrulation. Luciferase assays demonstrated that stbm inhibits Wnt-mediated activation of beta-catenin (116806)-dependent transcription while promoting phosphorylation of c-Jun- and AP1 (165160)-dependent transcription. From results of coimmunoprecipitation experiments, confocal microscopy analysis, and study of deletion mutants, Park and Moon (2002) concluded that stbm interacts with the Dsh protein (DVL1; 601365), which functions in both planar cell-polarity and beta-catenin pathways in Drosophila. In an erratum, Park and Moon (2002) reported that repeated gain-of-function and loss-of-function experiments in zebrafish embryos indicated that loss of anterior neural marker expression observed in their initial report was likely caused by cell death.
Montcouquiol et al. (2003) showed that a mutation in the Vangl2 gene results in significant disruptions in the polarization of stereociliary bundles in mouse cochlea as a result of defects in the direction of movement and/or anchoring of the kinocilium within each hair cell. Similar but less severe defects are observed in animals containing a mutation in the LAP protein family gene Scrb1 (607733). Polarization defects in animals heterozygous for Vangl2 and Scrb1 are comparable with Vangl2 homozygotes, demonstrating genetic interactions between these genes in the regulation of planar cell polarity in mammals.
Using yeast 2-hybrid assays, Yao et al. (2004) found that PDZ domain 1 of mouse Magi3 (615943) interacted with the C-terminal PDZ-binding motifs of Fzd4 (604579) and Fzd7 (603410), which function within the Wnt (see 116806) and PCP signaling pathways, and with Ltap, another PCP signaling protein. Magi3, Fzd4, and Ltap independently localized to sites of cell-cell contacts in epithelial cells, and these 3 proteins interacted in a complex that required Magi3. Magi3 strongly enhanced Rac (see 602048)-dependent Jnk (see 601158) activation by Fzd4 and Ltap.
Devenport and Fuchs (2008) found that marked changes in cell shape and cytoskeletal polarization occurred in embryonic mouse skin as nascent hair follicles became anteriorly angled, morphologically polarized, and molecularly compartmentalized along the anterior-posterior axis. Using embryonic mice harboring point mutations in Vangl2 and Celsr1 (604523), they showed that these proteins were asymmetrically distributed within the embryonic epidermal basal layer, were codependent for their asymmetric distribution, and drove the orientation of hair follicles along the anterior-posterior axis. Fzd6 (603409) was also required for the orientation of adult hair follicles. Fzd6 asymmetrically localized in the epidermis and was recruited to cell contacts by Celsr1. Devenport and Fuchs (2008) concluded that PCP proteins operate early in the mammalian epidermis to coordinately polarize hair follicles across body axes.
By removing both Vangl1 (610132) and Vangl2, the 2 mouse homologs of Drosophila core planar cell polarity (PCP) gene Van Gogh (Vang), Song et al. (2010) revealed a previously unrecognized function of PCP in the initial breaking of lateral symmetry. The leftward nodal flow across the posterior notochord is the earliest event in the de novo formation of left-right asymmetry. Song et al. (2010) showed that PCP is essential in interpreting the anterior-posterior patterning information and linking it to left-right asymmetry. In the absence of Vangl1 and Vangl2, cilia are positioned randomly around the center of the posterior notochord cells and nodal flow is turbulent, which results in disrupted left-right asymmetry. PCP in mouse, unlike what has been implicated in other vertebrate species, is not required for ciliogenesis, cilium motility, Sonic hedgehog (SHH; 600725) signaling, or apical docking of basal bodies in ciliated tracheal epithelial cells. Song et al. (2010) concluded that their data suggested that PCP acts earlier than the unidirectional nodal flow during bilateral symmetry breaking in vertebrates and provided insight into the functional mechanism of PCP in organizing the vertebrate tissues in development.
Shafer et al. (2011) found that both Dvl1 and Vangl2 were required for Wnt5a (164975)-stimulated outgrowth and anterior-posterior guidance of embryonic mouse and rat commissural axons. Dvl1 inhibited PCP signaling by increasing hyperphosphorylation of Frizzled-3 (FZD3; 606143), preventing its internalization. Vangl2 antagonized Fzd3 phosphorylation and promoted its internalization. In rat commissural axon growth cones, Vangl2 predominantly localized on the plasma membrane and was highly enriched on tips of filopodia, as well as in patches of membrane where new filopodia emerged. Shafer et al. (2011) proposed that the antagonistic functions of VANGL2 and DVL3 on FZD3 hyperphosphorylation and endocytosis sharpen PCP signaling at the tips of filopodia to sense directional Wnt signaling to cause turning of growth cones.
Lei et al. (2010) identified 3 different heterozygous missense mutations in the VANGL2 gene (see, e.g., 600533.0001 and 600533.0002) in 3 of 163 unrelated Chinese Han stillborn or miscarried fetuses with neural tube defects (182940), including anencephaly. The authors postulated that loss of function defects in this gene have a lethal effect during in utero development in humans, and noted loss of Vangl2 in mice results in defects of neural tube closure (see Torban et al. (2008)).
Kibar et al. (2011) sequenced the VANGL2 gene in a population-based study of 673 patients with various forms of neural tube defects. Six potentially pathogenic heterozygous missense mutations were identified in 7 patients, including 3 at positions that were absolutely conserved through zebrafish and Drosophila (R135W, R177H, and R270H), and 3 at positions that were highly conserved (L242V, T247M, and R482H). Two patients had open neural tube defects (NTDs) with myelomeningocele and 5 had closed NTDs, which was a statistically significant difference (p = 0.027). However, 2 unaffected parents carried 2 of the mutations, and another mutation (R105C) was found in 1 of 287 controls. Functional studies of the mutations were not performed. Kibar et al. (2011) suggested that variation in the VANGL2 gene may predispose to neural tube defects, but noted that the findings needed to be confirmed.
Lu et al. (2004) demonstrated that a mutation in the mouse protein tyrosine kinase-7 (PTK7; 601890) gene, which encodes an evolutionarily conserved transmembrane protein with tyrosine kinase homology, disrupts neural tube closure and stereociliary bundle orientation, and shows genetic interactions with a mutation in the mouse Van Gogh homolog Vangl2. Lu et al. (2004) also showed that PTK7 is dynamically localized during hair cell polarization, and that the Xenopus homolog of PTK7 is required for neural convergent extension and neural tube closure. Lu et al. (2004) concluded that their results identified PTK7 as a novel regulator of planar cell polarity in vertebrates.
The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration, and mitotic spindle orientation. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation. Ross et al. (2005) showed that mice with mutations in genes involved in Bardet-Biedl syndrome (209900), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects, and disrupted cochlear stereociliary bundles. Furthermore, they identified genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype resulted from enhanced defective convergent extension movements. They also showed that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggested that cilia are intrinsically involved in planar cell polarity processes.
Torban et al. (2008) created mice with an inactivating mutation in the Vangl1 gene (610132). Vangl1 showed a dynamic pattern of expression in the developing neural tube and notochord at the time of neural tube closure. Heterozygous and homozygous Vangl1 mutants were viable and fertile, although homozygous mutants displayed subtle alterations in polarity of inner hair cells of the cochlea. In contrast with healthy Vangl1 heterozygous mutants and mice heterozygous for the Vangl2 Lp mutation, mice heterozygous for both Vangl1 and Vangl2 mutations showed profound developmental defects, including severe craniorachischisis, inner ear defects, and cardiac abnormality. Torban et al. (2008) concluded that genetic interaction between Vangl1 and Vangl2 can cause neural tube defects.
Suriben et al. (2009) found that Dact1 (607861)-null mice were born at a near mendelian ratio, but, with rare exceptions, they died within a day of birth with severe posterior malformations. Defects included lack of anus, urinary outlet, and external genitalia, short tail, and variable malformations involving the kidneys, bladder, colon, and reproductive organs. Earliest detection of developmental malformation was on embryonic day 8.25, when Dact1 -/- mutants were misshapen posteriorly in the region of the primitive streak. Suriben et al. (2009) found that heterozygous mutation of Vangl2 rescued recessive Dact1 phenotypes. Conversely, loss of Dact1 rescued semidominant Vangl2 phenotypes. Coimmunoprecipitation analysis showed that Dact1 formed a complex with Vangl2. In Dact1 -/- mutants, Vangl2 was increased at the primitive streak, where cells ordinarily undergo an epithelial-mesenchymal transition, and this was associated with abnormal E-cadherin (CDH1; 192090) distribution and changes in biochemical measures of the PCP pathway. Suriben et al. (2009) concluded that DACT1 contributes to morphogenesis at the primitive streak by regulating VANGL2 upstream of cell adhesion and the PCP pathway.
Yates et al. (2010) showed that mutations in the planar cell polarity genes Celsr1 (604523) and Vangl2 led to disrupted lung development and defects in lung architecture in transgenic mice. Lungs from Celsr1(Crsh) and Vangl(2Lp) mouse mutants were small and misshapen with fewer branches, and by late gestation exhibited thickened interstitial mesenchyme and defective saccular formation. There was a recapitulation of these branching defects following inhibition of Rho kinase (601702), an important downstream effector of the PCP signaling pathway. Epithelial integrity was disrupted, cytoskeletal remodeling perturbed, and mutant endoderm did not branch normally in response to the chemoattractant FGF10 (602115). Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. The authors concluded that Celsr1 and Vangl2 are required for normal fetal lung development and may be key components of a novel signaling pathway critical for this process.
Yates et al. (2010) investigated metanephroi in Lp mice. Although ureteric bud formation was normal in Vangl2 Lp/Lp embryos, subsequent in vivo and in vitro branching morphogenesis was impaired. Null mutant kidneys were short, consistent with an embryonic convergent extension (CE) defect. Differentiating glomerular epithelia expressed several planar cell polarity (PCP) pathway genes (Vangl1/2; Celsr1; Scrib, 607733; Mpk1/2, see 608500/608501; and Fat4, 612411), and glomeruli in Vangl2 Lp/Lp fetuses were smaller and contained less prominent capillary loops than those of wildtype littermates. Vangl2 Lp/+ kidneys had modest reduction in glomerular numbers postnatally, and Vangl2 Lp/Lp metanephroi contained occasional dilated tubules but no overt cystic phenotype. Yates et al. (2010) concluded that a PCP gene (Vangl2) is required for normal morphogenesis of both the ureteric bud and metanephric mesenchyme-derived structures. They further suggested that PCP pathway mutations should be sought when neural tube defects and renal malformations coexist in humans.
Yin et al. (2012) found that compound Vangl2 Lp/- mutant mice had a more severe polarity defect in inner ear hair cells than did Vangl2 -/- mice. In transfected MDCK cells, Vangl2 interacted directly with Vangl1, and the Lp mutation (S464N) reduced membrane expression of cotransfected wildtype Vangl1 or Vangl2 and caused their retention in endoplasmic reticulum. Knockout of Vangl2 or expression of the Vangl2 Lp mutant also altered polarized expression of other PCP proteins in inner ear cells, but in different ways. Knockout of Vangl2 alone in mice did not alter apical expression of Vangl1 in mutant inner ear cells. Yin et al. (2012) concluded that Lp is a dominant mutation in mice.
Chen et al. (2013) identified a mutation in the mouse Vangl2 gene that was induced by N-ethyl-N-nitrosourea. The C-to-T transition in exon 8 introduced a premature stop at codon 449. Homozygous mutants showed craniorachischisis at embryonic day 18.5, and heterozygotes appeared normal, except for a looped tail.
In a Han Chinese male fetus with anencephaly and occipital and cervical spina bifida (182940) miscarried at 21 weeks' gestation, Lei et al. (2010) identified a heterozygous 1543C-T transition in the VANGL2 gene, resulting in an arg353-to-cys (R353C) substitution in the cytoplasmic domain adjacent to the C-terminal PDZ-binding domain. The mutation was not found in 508 controls. Yeast 2-hybrid analysis showed that the R353C-mutant protein had diminished interaction with DVL1 (601365) compared to wildtype.
In a Han Chinese male fetus with anencephaly (see 182940) miscarried at 24 weeks' gestation, Lei et al. (2010) identified a heterozygous 1796T-C transition in the VANGL2 gene, resulting in a phe437-to-ser (F437S) substitution in the cytoplasmic domain adjacent to the C-terminal PDZ-binding domain. The mutation was not found in 508 controls. Yeast 2-hybrid analysis showed that the F437S mutation completely abrogated interaction with DVL1 (601365) compared to wildtype.
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