Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders

Beaumont, Marie; Akloul, Linda; Carré, Wilfrid; Quēlin, Chloé; Journel, Hubert; Pasquier, Laurent; Fradin, Mélanie; Odent, Sylvie; Hamdi-Rozé, Houda; Watrin, Erwan; Dupé, Valérie; Dubourg, Christèle; David, Véronique

doi:10.1007/s00439-019-01993-y

Cited by 16 publications

(10 citation statements)

References 73 publications

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“…Deleterious genetic variants disrupting normal function of core PCP maintenance genes (e.g. CELSR1, DACT1, SCRIB and VANGL2) has been associated with ~ 20% of craniorachischisis cases and 8% of spina bifida cases 3,39 . The extent of non-canonical WNT/PCP gene variants identified from subjects affected by various types of NTDs was recently published 19 .…”

Section: Discussionmentioning

confidence: 99%

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

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.

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Section: Discussionmentioning

confidence: 99%

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

Au¹,

Hebert²,

Hillman³

et al. 2021

Sci Rep

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“…S5 ). These proteins are mainly associated with cellular junction, adhesion, mitosis, and proliferation as well as cytoskeleton proteins [ 107 ]; however, apart from FREM2 [ 108 , 109 ], the roles of the other proteins in NPC maintenance and function are not well documented [ 110 ]. According to previous studies, which highlighted the importance of cell-cell connections in NSPCs' biological behaviour [ 111–113 ], our data may bring the 3 differentially expressed desmosomal proteins, DSP, JUP, and PKP2, into the spotlight for further investigation of the impact of the desmosome junction on providing more desirable niches for NPC maintenance, proliferation, and differentiation.…”

Section: Data Descriptionmentioning

confidence: 99%

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

et al. 2020

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Background Generation of oligodendrocytes is a sophisticated multistep process, the mechanistic underpinnings of which are not fully understood and demand further investigation. To systematically profile proteome dynamics during human embryonic stem cell differentiation into oligodendrocytes, we applied in-depth quantitative proteomics at different developmental stages and monitored changes in protein abundance using a multiplexed tandem mass tag-based proteomics approach. Findings Our proteome data provided a comprehensive protein expression profile that highlighted specific expression clusters based on the protein abundances over the course of human oligodendrocyte lineage differentiation. We identified the eminence of the planar cell polarity signalling and autophagy (particularly macroautophagy) in the progression of oligodendrocyte lineage differentiation—the cooperation of which is assisted by 106 and 77 proteins, respectively, that showed significant expression changes in this differentiation process. Furthermore, differentially expressed protein analysis of the proteome profile of oligodendrocyte lineage cells revealed 378 proteins that were specifically upregulated only in 1 differentiation stage. In addition, comparative pairwise analysis of differentiation stages demonstrated that abundances of 352 proteins differentially changed between consecutive differentiation time points. Conclusions Our study provides a comprehensive systematic proteomics profile of oligodendrocyte lineage cells that can serve as a resource for identifying novel biomarkers from these cells and for indicating numerous proteins that may contribute to regulating the development of myelinating oligodendrocytes and other cells of oligodendrocyte lineage. We showed the importance of planar cell polarity signalling in oligodendrocyte lineage differentiation and revealed the autophagy-related proteins that participate in oligodendrocyte lineage differentiation.

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“…Several studies have been performed to test the genetic nature of NTD or SB. Beaumont et al (2019) found that targeted panel sequencing enabled detection of candidate pathogenic variants in up to 36% for 52 NTDs/SB individuals. However, they did not test for the presence or absence of these variants in a negative control population.…”

Section: Discussionmentioning

confidence: 99%

“…We deemed it likely that human SB may be caused by deleterious variants in monogenic genes, because of (i) the congenital nature of SB; (ii) familial occurrence of SB (Detrait et al, 2005); (iii) the existence of monogenic mouse models with SB (Table S2); (iv) the existence of SB as part of the phenotypic manifestation of known monogenic multiorgan syndromes (Table S4); and (v) the knowledge that specific master genes govern neural tube morphogenesis (Beaumont et al, 2019; Kibar et al, 2007; Torban et al, 2004; Wang et al, 2019). Several studies have been performed to explore the genetic nature of SB.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identifies potential candidate genes for spina bifida derived from mouse models

Wang

Seltzsam

Zheng

et al. 2022

American J of Med Genetics Pt A

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Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome‐wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome‐wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome‐wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

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Targeted panel sequencing establishes the implication of planar cell polarity pathway and involves new candidate genes in neural tube defect disorders

Cited by 16 publications

References 73 publications

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

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

The Dynamic Proteome of Oligodendrocyte Lineage Differentiation Features Planar Cell Polarity and Macroautophagy Pathways

Whole exome sequencing identifies potential candidate genes for spina bifida derived from mouse models

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