Mutation of the Planar Cell Polarity Gene VANGL1 in Adolescent Idiopathic Scoliosis

Andersen, Malene Rask; Farooq, Muhammad; Koefoed, Klaus; Kjaer, Klaus; Simony, Ane; Christensen, Søren Tvorup; Larsen, Lars Allan

doi:10.1097/brs.0000000000001927

Cited by 16 publications

(12 citation statements)

References 27 publications

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“…As cilia have been described as a potential factor in IS etiology ( Grimes et al 2016 ; Patten et al 2015 ; Buchan et al 2014b ; Andersen et al 2017 ; Einarsdottir et al 2017 ), we further investigated the cilia connections identified in our dataset. Cilia components and functions are still under active exploration by many groups, and as a result the cilia-related GO term annotations are not always up to date.…”

Section: Resultsmentioning

confidence: 99%

“…Defects in motile cilia (which generate the flow of extracellular fluid) can cause a late-onset scoliosis without vertebral malformations in zebrafish ( Hayes et al 2014 ; Grimes et al 2016 ), which was attributed to defects in cerebral spinal fluid flow ( Grimes et al 2016 ). Additional studies have also implicated basal body and cilia genes in IS etiology in humans and zebrafish ( POC5 , kif6 , VANGL1 , and CELSR2 ) ( Patten et al 2015 ; Buchan et al 2014b ; Andersen et al 2017 ; Einarsdottir et al 2017 ). Longer cilia were observed on osteoblasts from IS individuals when compared to controls, although the functional significance of this finding has not yet been determined ( Oliazadeh et al 2017 ).…”

Section: Discussionmentioning

confidence: 99%

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Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology

Baschal

Terhune

Wethey

et al. 2018

G3 Genes|Genomes|Genetics

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Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology

Baschal

Terhune

Wethey

et al. 2018

G3 Genes|Genomes|Genetics

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show abstract

“…This link was additionally uncovered in the study of zebrafish ptk7 mutants, which exhibit late-onset severe spinal curvature abnormalities that are likely due to defective cerebrospinal fluid flow, mediated by multiciliated cells 133,134 . A recent survey of a patient cohort with adolescent idiopathic scoliosis (AIS), which screened for mutations in VANGL1, identified two missense mutations of interest were identified as potentially contributing to the AIS phenotypes 135 .…”

Section: Introductionmentioning

confidence: 99%

Planar cell polarity in development and disease

Butler

Wallingford

2017

Nat Rev Mol Cell Biol

502

488

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Planar Cell Polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted Wnt ligands, and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking, and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.

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“…In mammals, PCP controls a diverse array of cellular, developmental, and physiological processes, such as directed cell migration, left-right patterning, arrangement of inner ear sensory hair cells, skeletal morphogenesis, axon guidance, and epidermal wound healing [1-4, 19, 27-33]. Dysregulation of PCP signaling in humans is associated with neural tube defects, neurological disorders (e.g., epilepsy), skeletal defects, and other human diseases, including cancer [24,[34][35][36][37][38][39][40][41]. For example, mutations in human ROR2, its ligand WNT5A, as well as DVL1 and DVL3 cause a severe skeletal dysplasia, Robinow syndrome [42][43][44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development

et al. 2017

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Planar cell polarity (PCP) is an evolutionarily conserved essential mechanism that provides directional information to control and coordinate polarized cellular and tissue behavior during embryonic development. Disruption of PCP leads to severe morphological defects in vertebrates and its dysregulation results in a variety of human diseases such as neural tube defects and skeletal dysplasia. PCP is governed by a set of highly conserved core proteins that are asymmetrically localized at the cell surface throughout the polarized tissues. The uniform directionality of PCP is established by global cues, such as Wg/Wnt signaling gradients that break the original symmetrical localization of core PCP proteins including Vang/Vangl and Fz/Fzd. However, the exact mechanism remains elusive. In this study, we found that Vangl2 phosphorylation, which was previously identified to be induced by Wnt5a signaling, is required for Vangl2 functions in mammalian PCP in multiple tissues. The in vivo activities of Vangl2 are determined by its phosphorylation level. Phospho-mutant Vangl2 exhibits dominant negative effects, whereas Vangl2 with reduced phosphorylation is hypomorphic. We show that Vangl2 phosphorylation is essential for its uniform polarization pattern. Moreover, serine/threonine kinases CK1ɛ and CK1δ are redundantly required for Wnt5a-induced Vangl2 phosphorylation. Dvl family members are also required for Wnt5a-induced Vangl2 phosphorylation by enhancing the interaction of CK1 and Vangl2. These findings demonstrate that induction of Vangl protein phosphorylation plays an essential role in transducing Wnt5a signaling to establish PCP in mammalian development, suggesting a phosphorylation-regulated "Vangl activity gradient" model in addition to the well-documented "Fz activity gradient" model in Wnt/PCP signaling.

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Mutation of the Planar Cell Polarity Gene VANGL1 in Adolescent Idiopathic Scoliosis

Abstract: 4.

Cited by 16 publications

References 27 publications

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology

Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology

Planar cell polarity in development and disease

Wnt-induced Vangl2 phosphorylation is dose-dependently required for planar cell polarity in mammalian development

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