Rare missense variants in <i>DVL1</i>, one of the human counterparts of the <i>Drosophila dishevelled</i> gene, do not confer increased risk for neural tube defects

Merello, Elisa; Kibar, Zoha; Allache, Redouane; Piatelli, Gianluca; Cama, Armando; Capra, Valeria; Marco, Patrizia De

doi:10.1002/bdra.23157

Cited by 3 publications

(3 citation statements)

References 24 publications

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“…We analyzed the role of the human orthologs DVL1 , DVL2 , and DVL3 in a cohort of 453 patients. We detected a total of fourteen rare mutations, five in DVL2 , three in DVL3 , and six in DVL1 that were not present in all controls analyzed (De Marco et al, ; Merello et al, ). However, there was no difference in the overall rate of deleterious variants between the patients and controls for DVL1 and DVL3 genes, demonstrating a possible role only for rare variants in DVL2 gene as risk factors for NTDS.…”

Section: Dishevelledmentioning

confidence: 95%

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Marco

Merello

Piatelli

et al. 2014

Birth Defects Research

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Neural Tube Defects (NTDs) are congenital malformations that involve failure of the neural tube closure during the early phases of development at any level of the rostro-caudal axis. The planar cell polarity (PCP) pathway is a highly conserved, noncanonical Wnt-Frizzled-Dishevelled signaling cascade, that was first identified in the fruit fly Drosophila. We are here reviewing the role of the PCP pathway genes in the etiology of human NTDs, updating the list of the rare and deleterious mutations identified so far. We report 50 rare nonsynonymous mutations of PCP genes in 54 patients having a pathogenic effect on the protein function. Thirteen mutations that have previously been reported as novel are now reported in public databases, although at very low frequencies. The mutations were private, mostly missense, and transmitted by a healthy parent. To date, no clear genotype-phenotype correlation has been possible to create. Even if PCP pathway genes are involved in the pathogenesis of neural tube defects, future studies will be necessary to better dissect the genetic causes underlying these complex malformations.

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Section: Dishevelledmentioning

confidence: 95%

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Marco

Merello

Piatelli

et al. 2014

Birth Defects Research

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“…Morphogenesis and closure of the neural tube is affected by nutritional, environmental and genetic factors including Wnt/PCP signaling, which is illustrated by genetic association between NTD in humans and mutations in the PCP genes VANGL1, VANGL2, CELSR1, FZD6 , and DVL2 (Cai and Shi, 2014 ; reviewed in De Marco et al, 2014 ). Notably, also mutations in DVL1 or DVL3 have been identified in humans with NTD (Figure 2 ), although the correlation was not significant (De Marco et al, 2013 ; Merello et al, 2013 ; Chen et al, 2016 ).…”

Section: Dvl Paralogs In Vertebrate Embryonic Developmentmentioning

confidence: 99%

“…Mutations are indicated at the positions of amino acid changes. Changes detected in individuals with NTDs (De Marco et al, 2013 ; Merello et al, 2013 ; Chen et al, 2016 ) are color coded orange (predicted pathogenic) and gray (predicted benign, in all cases A>V). All ADRS mutations are (−1)-frameshift mutations resulting in altered amino acid sequences in the C-terminus and a premature stop (Bunn et al, 2015 ; White et al, 2015 , 2016 ), which are indicated by hatched area and red line respectively.…”

Section: Dvl Paralogs In Vertebrate Embryonic Developmentmentioning

confidence: 99%

Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

Gentzel

Schambony

2017

Front. Cell Dev. Biol.

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Dishevelled (DVL) proteins are highly conserved in the animal kingdom and are important key players in β-Catenin-dependent and -independent Wnt signaling pathways. Vertebrate genomes typically comprise three DVL genes, DVL1, DVL2, and DVL3. Expression patterns and developmental functions of the three vertebrate DVL proteins however, are only partially redundant in any given species. Moreover, expression and function of DVL isoforms have diverged between different vertebrate species. All DVL proteins share basic functionality in Wnt signal transduction. Additional, paralog-specific interactions and functions combined with context-dependent availability of DVL isoforms may play a central role in defining Wnt signaling specificity and add selectivity toward distinct downstream pathways. In this review, we recapitulate briefly cellular functions of DVL paralogs, their role in vertebrate embryonic development and congenital disease.

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MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida

et al. 2016

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Dishevelled (DVL/Dvl) genes play roles in canonical and noncanonical Wnt signaling, both of which are essential in neural tube closing and are involved in balancing neural progenitor growth and differentiation, or neuroepithelial cell polarity, respectively. In mouse Dvl haploinsufficiency leads to neural tube defects (NTDs), which represent the second most common birth defects. However, DVL genes' genetic contributions in human NTDs are modest. We sought to explore the molecular impact on such genes in human NTDs in a Han Chinese cohort. In 47 cases with NTDs and 61 matched controls, in brain tissues, the DVL1/2 mRNA levels were correlated with the levels of a serine/threonine protein kinase MARK2, and in 20 cases with lumbosacral spina bifida, the mRNA levels of DVL1 and MARK2 were significantly decreased; by contrast, only an intronic rare variant was found. Moreover, in an extended population, we found merely three novel rare missense variants in 1 % of individuals with NTDs. In cell-based assays, Mark2 depletion indeed reduces Dvl gene expression and interrupts neural stem cell (NSCs) growth and differentiation, which are likely to be mediated through a decrease in class IIa HDAC phosphorylation and reduced H3K4ac and H3K27ac occupancies at the Dvl1/2 promoters. Finally, the detections of folate concentration in human brain tissue and NSCs and MEF cells indicates that folate deficiency contributes to the observed decreases in Mark2 and Dvl1 expression. Our present study raises a potential common pathogenicity mechanism in human lumbosacral spina bifida about DVL genes rather than their genetic pathogenic role.

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Rare missense variants in DVL1, one of the human counterparts of the Drosophila dishevelled gene, do not confer increased risk for neural tube defects

Abstract: Our findings did not provide evidence for the implication of DVL1 in the pathogenesis of human NTDs.

Cited by 3 publications

References 24 publications

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population

Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

MARK2/Par1b Insufficiency Attenuates DVL Gene Transcription via Histone Deacetylation in Lumbosacral Spina Bifida

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