Role of the planar cell polarity gene <i>Protein tyrosine kinase 7</i> in neural tube defects in humans

Wang, Mingqin; Marco, Patrizia De; Merello, Elisa; Drapeau, Pierre; Capra, Valeria; Kibar, Zoha

doi:10.1002/bdra.23422

Cited by 30 publications

(22 citation statements)

References 24 publications

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“…PTK7 was identified as a gene upregulated in colon carcinoma cells and appears to be misregulated in a variety of cancers (Dunn and Tolwinski, 2016). Furthermore, PTK7 mutations have recently been implicated in the etiology of neural tube defects and scoliosis (Hayes et al, 2014; Wang et al, 2015). Here, we will briefly describe these respective disorders and look at the human PTK7 gene variants identified in this context as well as their functional implications.…”

Section: Ptk7 and Diseasementioning

confidence: 99%

“…Indeed, rare mutations with a predicted damaging role were identified for a number of PCP genes including Vangl1/2, Celsr1, Fzd6, Dvl2, Prickle, and Scribble (Kibar et al, 2007; De Marco et al, 2014). Furthermore, the analysis of a cohort of 473 patients with various forms of neural tube defects identified six rare PTK7 sequence variants (Wang et al, 2015). Interestingly, five of these mutations are located in the extracellular domain of PTK7, which serves as interaction site for Wnt ligands as well as Fz7 and Ror2 receptors (Table 2; Peradziryi et al, 2011; Martinez et al, 2015; Podleschny et al, 2015).…”

Section: Ptk7 and Diseasementioning

confidence: 99%

“…Interestingly, this conserved P545 residue is also mutated in one of the six sequence variants identified in patients with neural tube closure defects. In a patient affected with myelomeningocele and interestingly also hydrocephalus, which is indicative of a cilia-defect, the non-polar proline residue was changed to a positively charged arginine (Wang et al, 2015). These data indicate that this conserved residue is important for protein function and mutations are likely pathogenic.…”

Section: Ptk7 and Diseasementioning

confidence: 99%

“…Additionally its function in adult tissue homeostasis is demonstrated by the fact that misregulation of PTK7 expression correlates with development of cancer and its progression to metastasis in various cellular contexts (reviewed in Dunn and Tolwinski, 2016). Furthermore, mutations in PTK7 have been implicated in scoliosis and human neural tube closure defects, demonstrating its clinical relevance (Hayes et al, 2014; Wang et al, 2015; Grimes et al, 2016). Since the first publication on PTK7/CCK-4 (Mossie et al, 1995) more than 20 years ago over 120 publications have followed.…”

Section: Introductionmentioning

confidence: 99%

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PTK7 Faces the Wnt in Development and Disease

Berger

Wodarz

Borchers

2017

Front. Cell Dev. Biol.

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PTK7 (protein tyrosine kinase 7) is an evolutionarily conserved transmembrane receptor regulating various processes in embryonic development and tissue homeostasis. On a cellular level PTK7 affects the establishment of cell polarity, the regulation of cell movement and migration as well as cell invasion. The PTK7 receptor has been shown to interact with ligands, co-receptors, and intracellular transducers of Wnt signaling pathways, pointing to a function in the fine-tuning of the Wnt signaling network. Here we will review recent findings implicating PTK7 at the crossroads of Wnt signaling pathways in development and disease.

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Section: Ptk7 and Diseasementioning

confidence: 99%

Section: Ptk7 and Diseasementioning

confidence: 99%

Section: Ptk7 and Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PTK7 Faces the Wnt in Development and Disease

Berger

Wodarz

Borchers

2017

Front. Cell Dev. Biol.

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“…Many recent studies have implicated rare genetic variants as contributing major effects in common complex diseases (Cirulli & Goldstein, ). Indeed, approaches used to scan through sequences of candidate genes in exomes of affected subjects have identified rare deleterious genetic variants potentially contributing to some human NTDs (Connealy, Northrup, & Au, ; De Marco et al, ; Lemay et al, ; Ruggiero, Northrup, & Au, ; Wang, De Marco, et al, ). The impact of the FA fortification mandate on the penetrance of variants in genes rescuable by FA should be carefully weighed when designing studies to identify these variants.…”

Section: Genetic Etiology Of Human Ntdsmentioning

confidence: 99%

Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

Findley

2017

American J of Med Genetics Pt A

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Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 – 200 per 10,000 births with the United States of American NTD incidence at around 3–6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35–50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.

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Variants identified in PTK7 associated with neural tube defects

Lei

Kim

Chen

et al. 2019

Molec Gen & Gen Med

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Background Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7XST87 and Vangl2Lp mutations present with spina bifida. Methods In this study, we initially sequenced exons of the human PTK7 gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function. Results We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted‐to‐be‐damaging variant or function‐disrupted PTK7 variant was identified among the control subjects. We subsequently re‐sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls. Conclusion Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.

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Role of the planar cell polarity gene Protein tyrosine kinase 7 in neural tube defects in humans

Abstract: We detected potentially pathogenic PTK7 variants in 1.1% of our NTD cohort. Our findings implicate PTK7 as a risk factor for NTDs and provide additional evidence for a pathogenic role of PCP signaling in these malformations.

Cited by 30 publications

References 24 publications

PTK7 Faces the Wnt in Development and Disease

PTK7 Faces the Wnt in Development and Disease

Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

Variants identified in PTK7 associated with neural tube defects

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