Expanding the mutational spectrum associated to neural tube defects: Literature revision and description of novel <i>VANGL1</i> mutations

Merello, Elisa; Mascelli, Samantha; Raso, Alessandro; Piatelli, Gianluca; Consales, Alessandro; Cama, Armando; Kibar, Zoha; Capra, Valeria; Marco, Patrizia De

doi:10.1002/bdra.23305

Cited by 31 publications

(21 citation statements)

References 64 publications

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“…Interestingly, increased expression of the VANGL2 homologue VANGL1 has been linked to tumor progression and increased malignancy [72, 73]. While both VANGL2 and VANGL1 regulate neural tube closure [74], only VANGL2 is required for PCP during zebrafish gastrulation [75]. Clearly, much remains to be learned about these transmembrane proteins and their functions during embryonic development and cancer progression.…”

Section: Discussionmentioning

confidence: 99%

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

Jessen

2017

Experimental Cell Research

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Planar cell polarity (PCP) proteins are implicated in a variety of morphogenetic processes including embryonic cell migration and potentially cancer progression. During zebrafish gastrulation, the transmembrane protein Vang-like 2 (VANGL2) is required for PCP and directed cell migration. These cell behaviors occur in the context of a fibrillar extracellular matrix (ECM). While it is thought that interactions with the ECM regulate cell migration, it is unclear how PCP proteins such as VANGL2 influence these events. Using an in vitro cell culture model system, we previously showed that human VANGL2 negatively regulates membrane type-1 matrix metalloproteinase (MMP14) and activation of secreted matrix metalloproteinase 2 (MMP2). Here, we investigated the functional relationship between VANGL2, integrin αvβ3, and MMP2 activation. We provide evidence that VANGL2 regulates cell surface integrin αvβ3 expression and adhesion to fibronectin, laminin, and vitronectin. Inhibition of MMP14/MMP2 activity suppressed the cell adhesion defect in VANGL2 knockdown cells. Furthermore, our data show that MMP14 and integrin αv are required for increased proteolysis by VANGL2 knockdown cells. Lastly, we have identified integrin αvβ3 as a novel VANGL2 binding partner. Together, these findings begin to dissect the molecular underpinnings of how VANGL2 regulates MMP activity and cell adhesion to the ECM.

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Section: Discussionmentioning

confidence: 99%

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

Jessen

2017

Experimental Cell Research

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“…Genetic studies of mice have identified more than 240 genes involved in neural tube closure (Harris & Juriloff, 2010;Wilde, Petersen, & Niswander, 2014;Wilson, & Maden, 2005) and this information has provided a framework to explore the genetic causes of NTDs in humans over the past decade (Chen et al, 2017;De Marco et al, 2014;Kibar et al, 2007;Qiao et al, 2016). Genes that function in particular pathways involved in planar cell polarity (PCP), ciliogenesis, the glycine cleavage system and one-carbon metabolism have been explored in a relatively large number of cases (Allache et al, 2015;Cai & Shi, 2014;De Marco et al, 2014;Dowdle et al, 2011;Hopp et al, 2011;Jones, Fiozzo, Waters, McKnight, & Brown, 2014;Kibar et al, 2007;Lei et al, 2013;Lei et al, 2014;Lei et al, 2010;Marini et al, 2011;Merello et al, 2015;Miao et al, 2016;Narisawa et al, 2012;Qiao et al, 2016;Roberson et al, 2015;Robinson et al, 2012;Shaheen et al, 2015;Yang et al, 2013;Zhang et al, 2015). PCP gene variants have been associated with the most severe NTD phenotype, craniorachischisis, as well as more limited NTDs such as myelomeningocele.…”

Section: Introductionmentioning

confidence: 99%

Genetic contribution of retinoid-related genes to neural tube defects

Zhang

Chen

et al. 2018

Human Mutation

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Rare variants are considered underlying causes of complex diseases. The complex and severe group of disorders called neural tube defects (NTDs) results from failure of the neural tube to close during early embryogenesis. Neural tube closure requires the coordination of numerous signaling pathways, including the precise regulation of retinoic acid (RA) concentration, which is controlled by enzymes involved in RA synthesis and degradation. Here, we used a case-control mutation screen study to reveal rare variants in retinoid-related genes in a Han Chinese NTD population by sequencing six genes in 355 NTD cases and 225 controls. More specific rare variants were found in exonic and upstream regions in NTD cases. The RA-responsive genes CYP26A1, CRABP1, and ALDH1A2 harbored NTD-specific rare variants in their upstream regions. Unexpectedly, the majority of missense variants in NTD cases were found in CYP26B1, which encodes a RA degradation enzyme, whereas no missense variants in this gene were found in controls. Functional analysis indicated that the CYP26B1 NTD variants were inefficient in the degradation of RA using assays of RA-induced transcription and RA-initiated neuronal differentiation. Our study supports the contribution of rare variants in RA-related genes to the etiology of human NTDs.

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“…Planar cell polarity genes play a critical role in neural tube closure in model organisms. Studies in humans have identified rare nonsynonymous mutations in planar cell polarity pathway genes, including the VANGL genes, that may play a role as risk factors for NTDs (Merello et al, ). Mutational analysis of three (patients 1, 2, 3) of four patients was performed.…”

Section: Discussionmentioning

confidence: 99%

Spinal lipoma as a dysembryogenetic anomaly: Four unusual cases of ectopic iliac rib within the spinal lipoma

Accogli

Pavanello

Accorsi

et al. 2016

Birth Defects Research

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We expand the clinical spectrum of fibrocartilaginous anomalies associated with spinal lipoma, suggesting the presence of an ectopic rib as a new possible phenotype in NTDs. A careful analysis by neuroradiologists and pathologists should be performed in spinal lipomas to assess the presence of an ectopic rib or other uncommon developmental anomalies. Furthermore, molecular studies are required to detect the genetic cause of this unusual phenotype. Birth Defects Research (Part A) 106:530-535, 2016. © 2016 Wiley Periodicals, Inc.

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Expanding the mutational spectrum associated to neural tube defects: Literature revision and description of novel VANGL1 mutations

Abstract: We showed a significant (p = 7.0E-5) association between VANGL1 rare genetic variants, especially missense mutations, and NTDs risk.

Cited by 31 publications

References 64 publications

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

VANGL2 interacts with integrin αv to regulate matrix metalloproteinase activity and cell adhesion to the extracellular matrix

Genetic contribution of retinoid-related genes to neural tube defects

Spinal lipoma as a dysembryogenetic anomaly: Four unusual cases of ectopic iliac rib within the spinal lipoma

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