Biallelic<i>ANGPT2</i>loss-of-function causes severe early-onset non-immune hydrops fetalis

Smeland, Marie Falkenberg; Brouillard, Pascal; Prescott, Trine; Boon, Laurence M.; Hvingel, B.; Nordbakken, Cecilie Valborg; Nystad, Mona; Holla, Øystein L.; Vikkula, Miikka

doi:10.1136/jmedgenet-2021-108179

Cited by 5 publications

(5 citation statements)

References 43 publications

(104 reference statements)

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“…Our study shows that Ang2-Tie signaling co-operates with the VEGF-C-VEGFR3 pathway involved in regulation of the development and growth of lymphatic capillaries and collecting vessels. Notably, our discovery that Ang2 and Tie1 are required for cell surface VEGFR3 expression in the cutaneous lymphatic capillaries is consistent with previous findings that loss-of-function mutations in Ang2, and possibly in Tie1, predispose to lymphedema and hydrops fetalis (29,30,58). In contrast, mutations of Ang1 and Tie2 have been found in glaucoma patients who have increased intraocular pressure and compromised function of the Schlemm's canal (SC), a lymphatic-like vessel that drains the intraocular fluid (59,60).…”

Section: Clinical Implications Of the Crosstalk Between Ang2-tie And ...supporting

confidence: 92%

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Korhonen¹,

Murtomäki²,

Jha³

et al. 2022

Journal of Clinical Investigation

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Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here we used gene deletion, blocking antibodies, transgene induction and gene transfer to study how Ang2, its Tie2 receptor and Tie1 regulate lymphatic vessels. We discovered that VEGF-C-induced Ang2 secretion from lymphatic endothelial cells (LECs) is involved in full Akt activation downstream of phosphoinositide-3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of Ang2 blocking antibody decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of PI3K catalytic p110α subunit or with small molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C-induced lymphangiogenesis also in adult mice. Our results reveal important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2-Tie-PI3K signaling.

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Section: Clinical Implications Of the Crosstalk Between Ang2-tie And ...supporting

confidence: 92%

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Korhonen¹,

Murtomäki²,

Jha³

et al. 2022

Journal of Clinical Investigation

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“…Evidence from previous studies has indicated that KRT23 influences the proliferation, migration, and prognosis of cancer ( Odena et al, 2016 ; Zhang et al, 2017 ; Chen et al, 2021 ). ANGPT2 is a ligand for TIE1–TIE2 signaling involved in the development and maintenance of blood and lymphatic vessels ( Smeland et al, 2021 ). In this study, we found that ANGPT2 regulates physiological and pathological angiogenesis in HNSCC by modulating vasodilation, microvascular permeability, and vasoconstriction ( Xu et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Nine-gene signature and nomogram for predicting survival in patients with head and neck squamous cell carcinoma

et al. 2022

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Background: Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal linings of the upper aerodigestive tract, salivary glands, thyroid, oropharynx, larynx, and hypopharynx. The present study aimed to identify the novel genes and pathways underlying HNSCC. Despite the advances in HNSCC research, diagnosis, and treatment, its incidence continues to rise, and the mortality of advanced HNSCC is expected to increase by 50%. Therefore, there is an urgent need for effective biomarkers to predict HNSCC patients’ prognosis and provide guidance to the personalized treatment.Methods: Both HNSCC clinical and gene expression data were abstracted from The Cancer Genome Atlas (TCGA) database. Intersecting analysis was adopted between the gene expression matrix of HNSCC patients from TCGA database to extract TME-related genes. Differential gene expression analysis between HNSCC tissue samples and normal tissue samples was performed by R software. Then, HNSCC patients were categorized into clusters 1 and 2 via NMF. Next, TME-related prognosis genes (p < 0.05) were analyzed by univariate Cox regression analysis, LASSO Cox regression analysis, and multivariate Cox regression analysis. Finally, nine genes were selected to construct a prognostic risk model and a prognostic gene signature. We also established a nomogram using relevant clinical parameters and a risk score. The Kaplan–Meier curve, survival analysis, time-dependent receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and the concordance index (C-index) were carried out to assess the accuracy of the prognostic risk model and nomogram. Potential molecular mechanisms were revealed by gene set enrichment analysis (GSEA). Additionally, gene correlation analysis and immune cell correlation analysis were conducted for further enriching our results.Results: A novel HNSCC prognostic model was established based on the nine genes (GTSE1, LRRN4CL, CRYAB, SHOX2, ASNS, KRT23, ANGPT2, HOXA9, and CARD11). The value of area under the ROC curves (AUCs) (0.769, 0.841, and 0.816) in TCGA whole set showed that the model effectively predicted the 1-, 3-, and 5-year overall survival (OS). Results of the Cox regression assessment confirmed the nine-gene signature as a reliable independent prognostic factor in HNSCC patients. The prognostic nomogram developed using multivariate Cox regression analysis showed a superior C-index over other clinical signatures. Also, the calibration curve had a high level of concordance between estimated OS and the observed OS. This showed that its clinical net can precisely estimate the one-, three-, and five-year OS in HNSCC patients. The gene set enrichment analysis (GSEA) to some extent revealed the immune- and tumor-linked cascades.Conclusion: In conclusion, the TME-related nine-gene signature and nomogram can effectively improve the estimation of prognosis in patients with HNSCC.

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“…Currently, however, 90% of cases are non‐immune hydrops fetalis (NIHF), affecting 1:1700–3000 pregnancies 3 . NIHF is caused by various etiologies, including infections, twin‐to‐twin transfusion, cardiovascular malformations, secondary to primary hydrothorax, chromosomal aberrations and genetic syndromes, particularly those causing lymphatic dysplasia 3‐5 . Indeed, genetic causes account for one third of NIHF cases, 25% of which can be detected by karyotype or chromosomal microarray (CMA) 3,4 .…”

Section: Figurementioning

confidence: 99%

“…3 NIHF is caused by various etiologies, including infections, twin-to-twin transfusion, cardiovascular malformations, secondary to primary hydrothorax, chromosomal aberrations and genetic syndromes, particularly those causing lymphatic dysplasia. [3][4][5] Indeed, genetic causes account for one third of NIHF cases, 25% of which can be detected by karyotype or chromosomal microarray (CMA). 3,4 In a series of 127 NIHF cases, Sparks et al (2020) 3 identified causative single-gene variants using exome sequencing (ES) in 37 cases (29%).…”

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confidence: 99%

Non‐immune hydrops fetalis caused by PIEZO1 compound heterozygous deletions detected only by exome sequencing

et al. 2022

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Key points What's already known about this topic? Genetic lymphatic disorders are a common cause of non‐immune hydrops fetalis, with PIEZO1 being one of the more recently established disease‐causing genes. What does this study add? Disease‐causing PIEZO1 variants have mostly been reported as single nucleotide variants or small indels. We report on a fetus with compound heterozygous deletions within and including PIEZO1. The deletions were not detected by chromosomal microarray (CMA). This case highlights the value of exome sequencing in detecting copy number variants that are below CMA resolution.

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BiallelicANGPT2loss-of-function causes severe early-onset non-immune hydrops fetalis

Cited by 5 publications

References 43 publications

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Nine-gene signature and nomogram for predicting survival in patients with head and neck squamous cell carcinoma

Non‐immune hydrops fetalis caused by PIEZO1 compound heterozygous deletions detected only by exome sequencing

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