Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Au, Kit Sing; Hebert, Luke; Hillman, Paul; Baker, Craig; Brown, M. R. W.; Kim, D.-K.; Soldano, Karen; Garrett, Melanie E.; Ashley-Koch, Allison E.; Lee, S.; Gleeson, Joseph G.; Hixson, James E.; Morrison, A. C.

doi:10.1038/s41598-021-83058-7

Cited by 13 publications

(7 citation statements)

References 66 publications

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“…Array-based comparative genomic hybridization of a cohort of 189 Caucasian and Hispanic cases with non-syndromic lumbo-sacral myelomeningocele identified heterozygous deletions of glypican genes GPC5 and GPC6 ( Bassuk et al, 2013 ) as a significant risk factor. Similarly, ultra-rare deleterious variants in the extracellular matrix genes FRAS1-related extracellular matrix 2 ( FREM2 ) and perlecan ( HSPG2 ) were found to be associated with myelomeningocele in a cohort of North American individuals ( Au et al, 2021 ). Interestingly, ingestion of chlorate in drinking water has been significantly associated with risk of spina bifida in Italy ( Righi et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Vangl2–environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

Nychyk

Galea

Molè

et al. 2022

Disease Models &Amp; Mechanisms

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Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs. We found that reduced sulfation of glycosaminoglycans interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause craniorachischisis in cultured mouse embryos, with rescue by exogenous sulphate. We hypothesised this glycosaminoglycan-PCP interaction may regulate CE but, surprisingly, DiO labeling of the embryonic node demonstrates no abnormality of midline axial extension in sulfation-depleted Lp/+ embryos. Positive-control Lp/Lp embryos show severe CE defects. Abnormalities were detected in the size and shape of somites that flank the closing neural tube in sulfation-depleted Lp/+ embryos. We conclude that failure of closure initiation can arise by a mechanism other than faulty neuroepithelial CE, with possible involvement of matrix-mediated somite expansion, adjacent to the closing neural tube.

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Section: Discussionmentioning

confidence: 99%

Vangl2–environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

Nychyk

Galea

Molè

et al. 2022

Disease Models &Amp; Mechanisms

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“…EP300 has been studied in mouse models of NTDs and is predicted to activate pathways that promote fusion of the neural tube 60,61 . In humans, rare deleterious variants in the EP300 gene have recently been associated with NTDs 62 , and here, EP300 was the dominant, nutrient-sensitive focal point for DEG regulation in cases. Two additional nutrient-dependent TFs identified here further support a role for both zinc and B vitamin-interacting gene dysregulation in cases: Sirtuin 6 ( SIRT6 ; vitamin B3- and zinc-dependent) and CHURC1 (zinc-dependent).…”

Section: Discussionmentioning

confidence: 65%

Identification of novel nutrient-sensitive gene regulatory networks in amniocytes from fetuses with spina bifida

White

Arif-Pardy

Connor

2022

Preprint

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Background: Neural tube defects (NTDs) remain among the most common congenital anomalies. Contributing risk factors include genetics and nutrient deficiencies, however, a comprehensive assessment of nutrient-gene interactions in NTDs is lacking. We hypothesised that multiple nutrient-gene interactions would be evident in NTD-associated gene signatures. Methods: We applied a novel, nutrient-focused gene expression analysis pipeline to identify nutrient-sensitive gene regulatory networks in amniocyte gene expression data (GSE4182) from fetuses with NTDs (cases; n=3) and fetuses with no congenital anomalies (controls; n=5). Differentially expressed genes (DEGs) were identified and screened for having nutrient cofactors. Transcription factors (TFs) with nutrient cofactors that regulated DEGs, and nutrient-sensitive miRNAs that had a previous link to NTDs, were identified and used to construct DEG regulatory networks. Results: Of the 880 DEGs in cases (vs. controls), 10% had at least one nutrient cofactor. DEG regulatory network analysis revealed that 39% and 52% of DEGs in cases were regulated by 22 nutrient-sensitive miRNAs and 10 nutrient-dependent TFs, respectively. Zinc- and B vitamin- dependent genes and gene regulatory networks (Zinc: 10 TFs targeting 50.6% of DEGs; B vitamins: 4 TFs [targeting 37.7% of DEGs], 9 miRNAs [targeting 17.6% of DEGs]) were dysregulated in cases. Two nutrient-dependent TFs predicted to target DEGs in cases (Tumor Protein 63 and Churchill Domain Containing 1) have not been previously linked to NTDs. Conclusions: We identified multiple novel nutrient-sensitive gene regulatory networks associated with NTDs, which may relate to NTD pathogenesis, and indicate new targets to explore for NTD prevention or to optimise fetal development.

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“…Array-based comparative genomic hybridization of a cohort of 189 Caucasian and Hispanic cases with non-syndromic lumbo-sacral myelomeningocele identified heterozygous deletions of glypican genes GPC5 and GPC6 (Bassuk et al, 2013), as a significant risk factor. Similarly, ultra-rare deleterious variants in the extracellular matrix genes FREM2 (FRAS1 Related Extracellular Matrix 2) and HSPG2 (perlecan) were found to be associated with myelomeningocele in a cohort of North American individuals (Au et al, 2021). Interestingly, ingestion of chlorate in drinking water has been significantly associated with risk of spina bifida in Italy (Righi et al, 2012).…”

Section: Discussionmentioning

confidence: 98%

Severe neural tube defects due to failure of closure initiation can arise without abnormality of neuroepithelial convergent extension

Nychyk

Galea

Molè

et al. 2021

Preprint

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Planar cell polarity (PCP) signalling is vital for initiation of neural tube closure in mice, with diminished convergent extension (CE) cell movements leading to a severe form of neural tube defect (NTD), termed craniorachischisis (CRN). Some human NTDs are also associated with PCP gene mutations, but affected individuals are generally heterozygous, whereas PCP homozygosity or compound heterozygosity is needed to produce CRN in mice. This suggests human NTDs may involve other genetic or environmental factors, that interact with partial loss of PCP function. We found that reduced sulfation OF glycosaminoglycans (GAGs) interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause CRN in mice. Here, we hypothesised that this GAG-PCP interaction may regulate convergent extension movements, and hence lead to severe NTDs in the context of only partial loss of PCP function. Both Lp and null alleles of Vangl2 gave similar findings. Culture of E8.5 embryos in the presence of chlorate (a GAG sulfation inhibitor), or enzymatic cleavage of GAG chains, led to failure of NT closure initiation in the majority of Lp/+ embryos, whereas few +/+ littermates exhibited CRN. The chlorate effect was rescued by exogenous sulphate. Surprisingly, DiO labeling of the embryonic node demonstrated no abnormality of midline axial extension in chlorate-treated Lp/+ embryos that developed CRN. In contrast, positive control Lp/Lp embryos displayed severe convergent extension defects in this assay. Morphometric analysis of the closure initiation site revealed abnormalities in the size and shape of somites that flank the closing neural tube in chlorate-treated Lp/+ embryos. We conclude that severe NTDs involving failure of closure initiation can arise by a mechanism other than faulty neuroepithelial convergent extension. Matrix-mediated expansion of somites, flanking the closing neural tube, may be required for closure initiation.

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Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration

Cited by 13 publications

References 66 publications

Vangl2–environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

Vangl2–environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension

Identification of novel nutrient-sensitive gene regulatory networks in amniocytes from fetuses with spina bifida

Severe neural tube defects due to failure of closure initiation can arise without abnormality of neuroepithelial convergent extension

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