A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene

Guyot, Marie-Claude; Bosoi, Ciprian M.; Kharfallah, Fares; Reynolds, Annie; Drapeau, Pierre; Justice, Monica J.; Gros, Philippe; Kibar, Zoha

doi:10.1002/dvdy.22577

Cited by 22 publications

(18 citation statements)

References 38 publications

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“…The p.Ile681Arg mutation was also detected by EcoRV digestion on Lrp6-exon9 PCR product and visualized on 2% agarose gel. For the Vangl2 Lp mutation, genotyping was done by PCR amplification on genomic DNA for Vangl2-exon 7 (360 bp) as previously described (48).…”

Section: Dna Extraction and Genotypingmentioning

confidence: 99%

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Allache

Lachance

Guyot

et al. 2013

Human Molecular Genetics

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Wnt signaling has been classified as canonical Wnt/b-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor -related protein Lrp6 is crucial for the activation of the Wnt/b-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26 m1Jus ) and in human NTDs. We demonstrate that Skax26 m1Jus represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6Skax26-Jus genetically interacts with a PCP mutant (Vangl2 Lp ) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.

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Section: Dna Extraction and Genotypingmentioning

confidence: 99%

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Allache

Lachance

Guyot

et al. 2013

Human Molecular Genetics

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“…Three independent mutant alleles have been described for Lp mice: the naturally occurring Lp (Strong and Hollander, 1949) (Murdoch et al, 2001;Guyot et al, 2011). We identified a novel ENU-induced Lp mutant mouse.…”

Section: Discussionmentioning

confidence: 94%

Loop-tail phenotype in heterozygous mice and neural tube defects in homozygous mice result from a nonsense mutation in the Vangl2 gene

Chen¹,

Mao²,

Chen³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. N-ethyl-N-nitrosourea (ENU) is a powerful point mutagen that can generate random mutations. It has been used to generate mouse mutations to produce phenotypic models of human disease. Neural tube defects (NTD) are common birth defects in which the brain and/or spinal cord can be exposed; however, the mechanisms of these defects are poorly understood. Craniorachischisis is one type of NTD that bears a close resemblance to the phenotype of the looptail (Lp) mouse. Here we describe a C57BL/6J Lp mouse generated by ENU-induced mutagenesis. The mutation was mapped to the Vangl2 gene on chromosome 1, near markers D1Mit113 and D1Mit149. Sequence analysis of Vangl2 heterozygotes (Vangl2 m1Yzcm /+) revealed a C/T transition mutation that resulted in substitution of a glutamine codon for a stop (nonsense) codon at position 449. The Vangl2 protein is involved in epithelium planar cell polarity. The predicted truncated protein would lack the PDZ-domain binding motif involved in proteinprotein interaction; therefore, Vangl2 m1Yzcm may be a loss-of-function mutant. Morphological and histological examination of homozygous

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“…Another possible mutational hot spot region in VANGL proteins may map downstream of the TM4 domain at the beginning of the C-terminal cytoplasmic tail. The VANGL1(Arg274Gln) mutant [Kibar et al, 2007], 3 VANGL2 mutants (p.Leu242Val, p.Thr247Met, p.Arg270His) and 2 of the 3 murine Vangl2 mutations (Asp255Glu, Arg259Leu) [Iliescu et al, 2011;Guyot et al, 2011] locate to this region and 3 of these 6 mutations modify arginine residues ( fig. 2 A).…”

Section: Discussionmentioning

confidence: 99%

“…Genes in the PCP pathway include Frizzled , Scrb1 , Dishevelled , Celsr1/ Flamingo , Prickle , Diego and Strabismus/VanGogh ( Stbm/ Vang ) [Copp et al, 2003;Harris and Juriloff, 2010]. In the Looptail mouse, homozygotes for some Vangl2 mutants (Ser464Asn, Asp255Glu) display a lethal NTD, craniorrhachischisis [Kibar et al, 2001;Iliescu et al, 2011], whereas homozygotes for a hypomorphic Vangl2 allele (Arg259Leu) may also show milder, spinal NTDs [Guyot et al, 2011]. The first human mutations in developmental genes implicated in the causation of NTDs were detected in the VANGL1 gene [Kibar et al, 2007].…”

mentioning

confidence: 99%

Novel <b><i>VANGL1</i></b> Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects

Bartsch

Kirmes²,

Thiede³

et al. 2012

Mol Syndromol

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Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system occurring at an average rate of 1 per 1,000 human pregnancies worldwide. Numerous genetic and environmental factors are discussed to be relevant in their etiology. In mice, mutants in >200 genes including the planar cell polarity (PCP) pathway are known to cause NTDs, and recently, heterozygous mutations in the human VANGL1 gene have been described in a small subset of patients with NTDs. We performed a VANGL1 mutation analysis in 144 unrelated individuals with NTDs from Slovakia, Romania and Germany and identified 3 heterozygous missense mutations: c.613G>A (p.Gly205Arg) with an open spina bifida (lumbosacral meningomyelocele), c.557G>A (p.Arg186His) with a closed spina bifida (tethered cord and spinal lipoma) and c.518G>A (p.Arg173His) with an unknown NTD. The c.613G>A mutation was also found in a healthy sibling. None of the mutations were described previously. Findings support that heterozygous VANGL1 mutations represent hypomorphs or conditional mutants predisposing to NTDs and occur at a frequency of approximately 2.1% of open and closed spinal NTDs. The mutations (p.Arg173His, p.Arg186His, p.Gly205Arg) modified conserved regions of the VANGL1 protein and shared similarities with previously described mutants, providing further evidence for the presence of mutational hot spots in these patients.

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A novel hypomorphic Looptail allele at the planar cell polarity Vangl2 gene

Cited by 22 publications

References 38 publications

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway

Loop-tail phenotype in heterozygous mice and neural tube defects in homozygous mice result from a nonsense mutation in the Vangl2 gene

Novel <b><i>VANGL1</i></b> Gene Mutations in 144 Slovakian, Romanian and German Patients with Neural Tube Defects

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