Role of the planar cell polarity gene <i>CELSR1</i> in neural tube defects and caudal agenesis

Allache, Redouane; Marco, Patrizia De; Merello, Elisa; Capra, Valeria; Kibar, Zoha

doi:10.1002/bdra.23002

Cited by 89 publications

(90 citation statements)

References 22 publications

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“…In the mouse, homozygous mutants for Celsr1 exhibit craniorachischisis, where the neural tube remains open from the midbrain/hindbrain boundary extending throughout the spinal region, and CELSR1 rare variants seem to have a significant role in the etiology of craniorachischisis [39]. Cases with myelomeningocele, lipomyelomeningocele, lipomyelocele, and lipoma were also found to have rare variants at CELSR1 [22]. There are three digenic combinations reported involving Celsr1 (with Vangl2, Ptk7 and Scrib) , all of which are doubly heterozygous variants, and caused craniorachischisis and spina bifida in mice [2,40,41].…”

Section: Discussionmentioning

confidence: 99%

Digenic variants of planar cell polarity genes in human neural tube defect patients

Wang

Xiao

Tian

et al. 2018

Molecular Genetics and Metabolism

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Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of < 0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.

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Section: Discussionmentioning

confidence: 99%

Digenic variants of planar cell polarity genes in human neural tube defect patients

Wang

Xiao

Tian

et al. 2018

Molecular Genetics and Metabolism

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“…We and others have previously demonstrated an important role for PCP signaling in the pathogenesis of NTDs where novel and rare mutations in PCP genes including VANGL1, PK1, FZD6, FUZZY, SCRIBBLE1 and CELSR1 were associated with NTDs in a subset of patients (37)(38)(39)(40)(41)(42). All these genes are activators of the PCP pathway, and some mutations were hypothesized to be hypomorphic.…”

Section: Novel Rare Mutations In Lrp6 Are Associated With Human Ntdsmentioning

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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“…Mutations in ADGRC1 (CELSR1) cause neural tube defects as well as caudal agenesis in humans (Allache et al, 2012;Robinson et al, 2012). Similarly, mice with missense mutations in Adgrc1 (Celsr1) show craniorachischisis, a severe neural tube defect (Curtin et al, 2003).…”

Section: Skeletal Muscle and Bonementioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

et al. 2015

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Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis

Cited by 89 publications

References 22 publications

Digenic variants of planar cell polarity genes in human neural tube defect patients

Digenic variants of planar cell polarity genes in human neural tube defect patients

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

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

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