The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases

Monaghan, Richard M.; Page, Donna J.; Østergaard, Pia; Keavney, Bernard

doi:10.1093/cvr/cvaa291

Cited by 33 publications

(19 citation statements)

References 145 publications

(166 reference statements)

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“…The FLT4 gene encodes VEGFR3 , which regulates the development and maintenance of lymphatic system ( Monaghan et al, 2021 ). The VEGFR3 acts as a cell-surface tyrosine kinase receptor for vascular endothelial growth factors C and D ( VEGFC and VEGFD ) ( Iljin et al, 2001 ; Leppanen et al, 2011 ; Gordon et al, 2013b ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: The compound heterozygotes variants in FLT4 causes autosomal recessive hereditary lymphedema in a Chinese family

et al. 2023

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Background: Lymphedema is a local form of tissue swelling, which is caused by excessive retention of lymph fluid in interstitial compartment caused by impaired lymphatic drainage damage. Primary lymphedema is caused by developmental lymphatic vascular abnormalities. Most cases are inherited as autosomal dominant, with incomplete penetrance and variable expression. Here we report compound heterozygotes variants in FLT4 of a Chinese family associated with primary lymphedema display autosomal recessive inheritance.Case presentation: Trio-whole-exome sequencing (Trio-WES) was performanced to analyse the underlying genetic cause of a proband with primary lymphedema in a Chinese family. Sanger sequencing was used to validate the variants in proband with primary lymphedema and members of the family with no clinical signs and symptoms. We reported compound heterozygotes for the Fms Related Receptor Tyrosine Kinase 4 (FLT4) gene detected in the proband, who carrying two different point variants. One was a missense variant (NM_182925.5; c.1504G>A, p.Glu502Lys), and the other was a recurrent variant (NM_182925.5; c.3323_3325del, p.Phe1108del). The missense variant c.1504G>A was detected in the proband, unaffected father, and unaffected paternal grandmother but not detected in unaffected paternal grandfather. The recurrent variant c.3323_3325del was detected in the proband, unaffected mother, and unaffected maternal grandfather but not detected in unaffected maternal grandmother. Our results suggests the possibility of an autosomal recessive inherited form of primary lymphedema resulting from variants of FLT4 encoding the vascular endothelial growth factor receptor-3.Conclusion: The results of the present study identifed compound heterozygotes FLT4 variants in a family with primary lymphedema which provides more information for autosomal recessive primary lymphedema caused by FLT4.

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Section: Discussionmentioning

confidence: 99%

Case Report: The compound heterozygotes variants in FLT4 causes autosomal recessive hereditary lymphedema in a Chinese family

et al. 2023

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“…The FLT4 mutations identified in patients with the tetralogy of Fallot are mainly missense or truncating variants in extracellular domains. Nevertheless, all the FLT4 mutations (missense or small in-frame deletions) known to cause Milroy disease have been located in 2 intracellular kinase domains (exons 17–26) and are assumed to interfere with the tyrosine kinase activation of the VEGFR3 receptor [ 15 , 58 ]. The mutations within the tyrosine kinase domains of the VEGFR3 receptor lead to decreased tyrosine kinase activity [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Patients with the tetralogy of Fallot have inherited a variant of the FLT4 gene from an asymptomatic parent, indicating that the mutant allele has reduced penetrance. Although the tetralogy of Fallot is seldom inherited in a Mendelian fashion, the penetrance of susceptibility variants is influenced by environmental and genetic factors [ 15 , 59 ]. In the current study, we detected a novel pathogenic variant in the FLT4 gene, which was associated with pulmonary atresia and ventricular septal defects in the first family.…”

Section: Discussionmentioning

confidence: 99%

“…Vascular endothelial growth factor 3 (VEGFR3) is encoded by the fms-like tyrosine kinase-4 ( FLT4 ; 136,352) gene, involved in the development of the lymphatic system. FLT4 variants cause Milroy disease (153,100), one of the main forms of hereditary primary lymphedema, and they also predispose to the tetralogy of Fallot, indicating the role of VEGFR3 in the primary development of the heart [ 15 ]. The protein-tyrosine phosphatase, non-receptor type 11 ( PTPN11 ; 176,876) gene encodes the non-receptor type protein tyrosine phosphatase SHP-2 (src homology region 2 domain phosphatase–2), which accounts for nearly 50% of cases with Noonan syndrome.…”

Section: Introductionmentioning

confidence: 99%

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A novel stop-gain pathogenic variant in FLT4 and a nonsynonymous pathogenic variant in PTPN11 associated with congenital heart defects

et al. 2022

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Background Congenital heart defects (CHDs) are the most common congenital malformations, including structural malformations in the heart and great vessels. CHD complications such as low birth weight, prematurity, pregnancy termination, mortality, and morbidity depend on the type of defect. Methods In the present research, genetic analyses via whole-exome sequencing (WES) was performed on 3 unrelated pedigrees with CHDs. The candidate variants were confirmed, segregated by PCR-based Sanger sequencing, and evaluated by bioinformatics analysis. Results A novel stop-gain c.C244T:p.R82X variant in the FLT4 gene, as well as a nonsynonymous c.C1403T:p.T468M variant in the PTPN11 gene, was reported by WES. FLT4 encodes a receptor tyrosine kinase involved in lymphatic development and is known as vascular endothelial growth factor 3. Conclusions We are the first to report a novel c.C244T variant in the FLT4 gene associated with CHDs. Using WES, we also identified a nonsynonymous variant affecting protein-tyrosine phosphatase, the non-receptor type 11 (PTPN11) gene. The clinical implementation of WES can determine gene variants in diseases with high genetic and phenotypic heterogeneity like CHDs.

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“…Interestingly, the identified mutations are distinct from those affecting Flt4 in Milroy's disease, an autosomal dominant form of congenital primary lymphedema. However, given that VEGFR3 during embryonic development is not yet restricted to LECs, and thus, has a role that goes beyond regulation of lymphangiogenesis, it remains to be determined whether indeed cardiac lymphatic alterations, rather than composite blood vascular dysfunction, are directly linked to developmental defects of the heart [17].…”

Section: Cardiac Lymphatics During Embryonic Developmentmentioning

confidence: 99%

Cardiac lymphatics: state of the art

Heron

Ratajska

Bråkenhielm

2022

Current Opinion in Hematology

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Purpose of reviewThe beneficial role of cardiac lymphatics in health and disease has begun to be recognized, with both preclinical and clinical evidence demonstrating that lymphangiogenesis is activated in cardiovascular diseases. This review aims to summarize our current understanding of the regulation and impact of cardiac lymphatic remodeling during development and in adult life, highlighting emerging concepts regarding distinguishing traits of cardiac lymphatic endothelial cells (LEC).Recent findingsGenetic lineage-tracing and clonal analyses have revealed that a proportion of cardiac LECs originate from nonvenous sources. Further, these sources may vary between different regions of the heart, and could translate to differences in LEC sensitivity to molecular regulators. Several therapeutic approaches have been applied to investigate how lymphatics contribute to resolution of myocardial edema and inflammation in cardiovascular diseases. From these studies have emerged novel insights, notably concerning the cross-talk between lymphatics and cardiac interstitial cells, especially immune cells.SummaryRecent years have witnessed a significant expansion in our knowledge of the molecular characteristics and regulation of cardiac lymphatics. The current body of work is in support of critical contributions of cardiac lymphatics to maintain both fluid and immune homeostasis in the heart.

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The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases

Cited by 33 publications

References 145 publications

Case Report: The compound heterozygotes variants in FLT4 causes autosomal recessive hereditary lymphedema in a Chinese family

Case Report: The compound heterozygotes variants in FLT4 causes autosomal recessive hereditary lymphedema in a Chinese family

A novel stop-gain pathogenic variant in FLT4 and a nonsynonymous pathogenic variant in PTPN11 associated with congenital heart defects

Cardiac lymphatics: state of the art

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