Identification and characterization of novel rare mutations in the planar cell polarity gene<i>PRICKLE1</i>in human neural tube defects

Bosoi, Ciprian M.; Capra, Valeria; Allache, Redouane; Trinh, Vincent Q.; Marco, Patrizia De; Merello, Elisa; Drapeau, Pierre; Bassuk, Alexander G.; Kibar, Zoha

doi:10.1002/humu.21589

Cited by 77 publications

(78 citation statements)

References 18 publications

(25 reference statements)

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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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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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“…The atypical cadherin, Fmi resides on both distal and proximal edges, where it binds neighboring cells through heomophilic interactions (Usui et al, 1999;Shimada et al, 2001). Xenopus, zebrafish and the mouse, the same set of 'core PCP' proteins has been shown to regulate a plethora of early developmental events ranging from convergent extension movements during gastrulation, orientation of cochlear hair cell in the ear, neural tube closure, oriented cell division, lung branching, hair follicle alignment and polarized ciliary beating in the trachea and brain ventricles (Goodrich andStrutt, 2011, Gray et al, 2011;Zallen, 2007;Bosoi et al, 2011;De Marco et al, 2012;Kibar et al, 2009;Kibar et al, 2007;Rida and Chen, 2009;Wang and Nathans, 2007;Yates and Dean, 2007;Segalen and Bellaïche, 2009;Vladar et al, 2012) ( Fig.1.6.4.1). In all cases local modulation of cytoskeleton is crucial for the proper conduct of these processes.…”

Section: Mechanism Of Planar Cell Polarity (Pcp)mentioning

confidence: 99%

Controlled levels of canonical Wnt signaling are required for neural crest migration

Maj

Künneke

Loresch

et al. 2016

Developmental Biology

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“…Genetic studies of human craniorachischisis suggest an association with mutations in CELSR1 and SCRIB (59). Recently, PRICKLE1 and PRICKLE2 mutations were implicated as predisposing factors or risk modifiers for human spina bifida (60,61). Two reviews summarize the compelling evidence for PCP gene involvement in NTDs (62,63).…”

Section: Introductionmentioning

confidence: 99%

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Bassuk

Muthuswamy

Boland³

et al. 2012

Human Molecular Genetics

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Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.

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Identification and characterization of novel rare mutations in the planar cell polarity genePRICKLE1in human neural tube defects

Cited by 77 publications

References 18 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

Controlled levels of canonical Wnt signaling are required for neural crest migration

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

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