A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like PrimaryLymphedema.

A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like Primary Lymphedema.

Feb 2013

Gordon K, Schulte D, Brice G, Simpson MA, Roukens MG, van Impel AW, Connell F, Kalidas K, Jeffery S, Mortimer PS,Mansour S, Schulte-Merker S, Ostergaard P.

Source

1Department of Clinical Sciences, St George's University of London, Cranmer Terrace, London, N/A, SW17 0RE, UNITED KINGDOM.

Abstract

Rationale: Mutations in VEGFR3 (FLT4) cause Milroy Disease (MD), an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic MD, suggesting genetic heterogeneity. 

Objective: To investigate the underlying cause in patients with clinical signs resembling MD in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. 

Methods and Results: Exome sequencing of five such patients was performed and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in one proband. The variant co-segregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighbouring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. 

Conclusions: We propose that the mutation in VEGFC is causative for the MD-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.

PubMed

See also:  Lymphedema Gene VEGFC

Increased Interstitial Protein Because of Impaired Lymph Drainage Does Not Induce Fibrosis and Inflammation in Lymphedema.

Jan 2103

Markhus CE, Karlsen TV, Wagner M, Svendsen OS, Tenstad O, Alitalo K, Wiig H.

Source

Department of Biomedicine, University of Bergen, Norway.

Abstract

OBJECTIVE:

The pathophysiology of lymphedema is incompletely understood. We asked how transcapillary fluid balance parameters and lymph flow are affected in a transgenic mouse model of primary lymphedema, which due to an inhibition of VEGFR-3-Ig signaling lacks dermal lymphatics, and whether protein accumulation in the interstitium occurring inlymphedema results in inflammation.

METHODS AND RESULTS:

As estimated using a new optical-imaging technique, we found that this signaling defect resulted in lymph drainage in hind limb skin of K14-VEGFR-3-Ig mice that was 34% of the corresponding value in wild-type. The interstitial fluid pressure and tissue fluid volumes were significantly increased in the areas of visible swelling only, whereas the colloid osmotic pressure in plasma, and thus the colloid osmotic pressure gradient, was reduced compared to wild-type mice. An acute volume load resulted in an exaggerated interstitial fluid pressure response in transgenic mice. There was no accumulation of collagen or lipid in skin, suggesting that chronic edema presented in the K14-VEGFR-3-Ig mouse was not sufficient to induce changes in tissue composition. Proinflammatory cytokines (interleukin-2, interleukin-6, interleukin-12) in subcutaneous interstitial fluid and macrophage infiltration in skin of the paw were lower, whereas the monocyte/macrophage cell fraction in blood and spleen was higher in transgenic compared with wild-type mice.

CONCLUSIONS:

Our data suggest that a high interstitial protein concentration and longstanding edema is not sufficient to induce fibrosis and inflammation characteristic for the human condition and may have implications for our understanding of the pathophysiology of this condition.

A M A

Possible Genetic Predisposition to Lymphedema after Breast Cancer

Possible Genetic Predisposition to Lymphedema after Breast Cancer

Lymphat Res Biol. 2012

Beth Newman, Ph.D.,¹ Felicity Lose, Ph.D.,² Mary-Anne Kedda, Ph.D.,¹ Mathias Francois, Ph.D.,³ Kaltin Ferguson,² Monika Janda, Ph.D.,¹ Patsy Yates, Ph.D.,⁴ Amanda B. Spurdle, Ph.D.,^2,* and Sandra C. Hayes, PhD^1,*

^Abstract

Background

Known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicate a number of potential candidate genes to explore in relation to secondary lymphedema.

Methods and Results

We undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n=22) and those without lymphedema serving as controls (n=98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD,VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1 were selected for genotyping. Multiple SNPs within three receptor genes, VEGFR2, VEGFR3, and RORC, were associated with lymphedema defined by statistical significance statistical significance  or extreme risk estimates

Conclusions

These provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger datasets.

NIH

Genetics and Milroy Disease

FLT4/VEGFR3 and Milroy Disease: Novel Mutations, a Review of Published Variants and Database Update.

October 2012

Gordon K, Spiden SL, Connell FC, Brice G, Cottrell S, Short J, Taylor R, Jeffery S, Mortimer PS, Mansour S, Ostergaard P.

Source

Department of Cardiac and Vascular Sciences, St George's University of London, London, United Kingdom.

Abstract

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. 

Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype-phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. 

This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4.

PubMed

The genetics of vascular anomalies.

The genetics of vascular anomalies. 

August 21, 2012

Frigerio A, Stevenson DA, Grimmer JF.

Source

aDepartment of Human Physiology, University of Milan, Milan, Italy bDivision of Medical Genetics, Department of Pediatrics cDivision of Otolaryngology, University of Utah, Salt Lake City, Utah, USA.

Abstract

PURPOSE OF REVIEW:

To summarize clinically relevant findings in the genetic cause and gene expression of vascular anomalies.

RECENT FINDINGS:

Infantile hemangioma demonstrates familial clustering and is associated with atopic disease. Variable gene expression is seen in infantile hemangioma during proliferation and involution. Capillary malformation may be sporadic or inherited in an autosomal dominant pattern. Capillary malformation-arteriovenous malformation is caused by mutation in RASA1. Some inherited forms of lymphedema are due to mutation in VEGFR3. Venous malformation may be sporadic, paradominant, or autosomal dominant inheritance. Autosomal dominantly inherited forms of venous malformation are due to mutations in TIE2/TEK. Additionally, TIE2 somatic mutations have been identified in about half of sporadic venous malformations.

SUMMARY:

Multiple genes have been identified causing inherited forms of vascular anomalies including capillary malformations, venous malformations and lymphedema. Variable gene expression of infantile hemangioma during proliferation and involution may offer new therapeutic targets for treatment.

Otolaryngology and Head and Neck Surgery