User Tools

Site Tools


Lymphedema Gene FLT4

Related Terms: PCL; FLT41; LMPH1A; VEGFR3; Hereditary Lymphedema, Type I; Congenital Hereditary Lymphedema; Milroy Disease.

The FLT4 is is associated with primary congenital lymphedema, also referred to as Milroys Syndrome.

The nomal “function” of this gene is to provide instructions for making a protein called vascular endothelial growth factor receptor 3 (VEGFR-3). This regulate the development and maintenance of the lymphatic system.

The lymphatic system produces and transports fluids and immune cells throughout the body. VEGFR-3 is turned on (activated) by two proteins called vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor D (VEGF-D). When VEGF-C and VEGF-D attach (bind) to VEGFR-3, chemical signals are produced that regulate the growth, movement, and survival of lymphatic cells. (1)

The fascinating thing is that there have been 19 mutations of this gene that have been found to actually cause Milroy's.



(1) FLT4 Genetics Home Reference

See also:

Genetic Labs


Lab Details

Lab Details

FLT4 Gene - fms-related tyrosine kinase 4

Aliases & Descriptions fms-related tyrosine kinase 41 2 FLT412 PCL1 2 5 OTTHUMP000001615392 VEGFR31 2 5 OTTHUMP000002235112 Fms-like tyrosine kinase 42 3 OTTHUMP000002235122 Tyrosine-protein kinase receptor FLT42 3 soluble VEGFR3 variant 12 FLT-42 3 soluble VEGFR3 variant 22 VEGFR-32 3 soluble VEGFR3 variant 32 EC 8 vascular endothelial growth factor receptor 32 LMPH1A2 5 EC 2.7.108

External Ids: HGNC: 37671 Entrez Gene: 23242 Ensembl: ENSG000000372807 OMIM: 1363525 UniProtKB: P359163

Export aliases for FLT4 gene to outside databases Previous GC identifers: GC05M180162 GC05M181012 GC05M180139 GC05M180132 GC05M179962 GC05M174752

Entrez Gene summary for FLT4: This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. (provided by RefSeq)

UniProtKB/Swiss-Prot: VGFR3_HUMAN, P35916 Function: Receptor for VEGFC. Has a tyrosine-protein kinase activity

summary for FLT4: Vascular endothelial growth factor is a signaling protein involved in the regulation of angiogenesis and vasculogenesis. VEGF binds to and activates a receptor tyrosine kinase, VEGFR. Three VEGFR isoforms have been identified in humans; VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (Flt-4). VEGFR-2 mediates the majority of cellular responses to VEGF. VEGFR-1 is thought to modulate VEGFR-2 signaling or to act as a dummy/decoy receptor to sequester VEGF away from VEGFR-2.

Complete page:


FLT4 fms-related tyrosine kinase 4 [ Homo sapiens ]

Gene ID: 2324, updated on 4-Dec-2011


Official Symbol: FLT4provided by HGNC

Official Full Name: fms-related tyrosine kinase 4provided by HGNC

Primary source: HGNC:3767

See related: Ensembl:ENSG00000037280; HPRD:00636; MIM:136352; Vega:OTTHUMG00000130931

Gene type: protein coding:

RefSeq status: REVIEWED

Organism: Homo sapiens

Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo Also known as PCL; FLT41; LMPH1A; VEGFR3

Summary This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type IA. [provided by RefSeq, Jul 2008]

Genomic context

Location: 5q35.3

Sequence:Sequence : Chromosome: 5; NC_000005.9 (180028506..180076624, complement

See also: Epigenomics MapViewer

Complete Page: NCBi-NIH

Abstracts and Studies

The expression of vascular endothelial growth factor and its receptors (flt1/fms, flk1/KDR, flt4) and vascular endothelial growth inhibitor in the bovine uterus during the sexual cycle and their correlation with serum sex steroids.

June 2011

Sağsöz H, Saruhan BG. Source Dicle University, Department of Histology and Embryology, 21280, Diyarbakir-Turkey. Abstract The present study was conducted to demonstrate of the immunohistochemical localization of vascular endothelial growth factor (VEGF) and its receptors (flt1/fms, flk1/KDR and flt4) as well as vascular endothelial growth inhibitor (VEGI) and to determine the correlation of VEGF and its receptors and VEGI with serum sex steroids (estrogen and progesterone) in the bovine uterus during the sexual cycle. The stage of the estrous cycle in 30 Holstein cattle was assessed based on the gross and histological appearance of the ovaries and uterus and on blood steroid hormone levels. Tissue samples obtained from the uterus were fixed in 10% formaldehyde for routine histological processing. During both follicular and luteal phases, positive cytoplasmic and membrane staining was achieved for VEGF and its receptors (flt1/fms, flk1/KDR and flt4) as well as VEGI in the luminal and glandular epithelial cells, the connective tissue and smooth muscle cells, and the vascular endothelial cells and smooth muscle cells in the uterus. The intensity, proportional and total scores determined for VEGF and its receptors (flt1/fms and flt4) as well as VEGI were greater in the luminal and glandular epithelial cells compared to the connective tissue and smooth muscle cells (P < 0.05). Furthermore, the number and intensity of the flk1/KDR positive cells were greater among the connective tissue cells compared to the luminal and glandular epithelial cells (P < 0.05). As a result, it was determined that the expression of VEGF and its receptors as well as VEGI in the bovine uterus during the follicular and luteal phases varied with different cell types. This suggests that depending on the stage of the sexual cycle, these factors may mediate the establishment of an appropriate environment for the nutritional supply and implantation of the embryo primarily due to the stimulation of angiogenesis but also through the increase in the secretory activity of the epithelial cells in the uterus. Furthermore, this indicates that ovarian steroid hormones play a significant role in regulating the expression of VEGF and its receptors as well as VEGI.


Distribution of vascular endothelial growth factor receptor-3/Flt4 mRNA in adult rat central nervous system. Sept 2011

Hou Y, Shin YJ, Han EJ, Choi JS, Park JM, Cha JH, Choi JY, Lee MY.


Department of Anatomy, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, 137-701, Seoul, South Korea.


Vascular endothelial growth factor receptor (VEGFR)-3/Flt4 binds VEGF-C and VEGF-D with high affinity. It has been suggested to be involved in neurogenesis and adult neuronal function. However, little is known about the localization of VEGFR-3 in the adult central nervous system (CNS). The present study presents, to our knowledge, the first detailed mapping of VEGFR-3 mRNA expression in adult rat brain and spinal cord by using in situ hybridization and reverse transcription-polymerase chain reaction analysis (RT-PCR). Varying VEGFR-3 expression intensity was detected in functionally diverse nuclei, with the highest levels in the mitral cells of the olfactory bulb, piriform cortex, anterodorsal thalamic nucleus, several nuclei of the hypothalamus, and the brainstem cranial nerve nuclei. VEGFR-3 mRNA was abundantly expressed in the ventral motor neurons of the spinal cord and in some circumventricular organs such as the median eminence and the area postrema. Moreover, the locus coeruleus and some of the nuclei of the reticular formation showed moderate-to-high hybridization signals. VEGFR-3 expression appeared to be localized mostly within neurons, but weak labeling was also found in some astrocytes. In particular, VEGFR-3 was highly expressed in ependymal cells of the ventral third ventricle and the median eminence, which were co-labeled with vimentin but not with glial fibrillary acidic protein, suggesting that these cells are tanycytes. RT-PCR analysis revealed similar levels of VEGFR-3 expression in all regions of the adult rat CNS. The specific but widespread distribution of VEGFR-3 mRNA in the adult rat CNS suggests that VEGFR-3 functions more broadly than expected, regulating adult neuronal function playing important roles in tanycyte function.


Milroy's primary congenital lymphedema in a male infant and review of the literature.

May 2010

Kitsiou-Tzeli S, Vrettou C, Leze E, Makrythanasis P, Kanavakis E, Willems P.


“Choremeio” Research Laboratory of Medical Genetics, Children's Hospital “Aghia Sophia”, Thivon and Levadeias, 11527, Greece.


BACKGROUND: Milroy's primary congenital lymphedema is a non-syndromic primary lymphedema caused mainly by autosomal dominant mutations in the FLT4 (VEGFR3) gene. Here, we report on a 6-month-old boy with congenital non-syndromic bilateral lymphedema at both feet and tibias, who underwent molecular investigation, consisted of PCR amplification and DHPLC analysis of exons 17-26 of the FLT4 gene. The clinical diagnosis of Milroy disease was confirmed by molecular analysis showing the c.3109G>C mutation in the FLT4 gene, inherited from the asymptomatic father. This is a known missense mutation, which substitutes an aspartic acid into a histidine on amino acid position 1037 of the resulting protein (p.D1037H), described in two other families with Milroy disease. A thorough genetic molecular investigation and clinical evaluation contributes to the provision of proper genetic counseling for parents of an affected child with Milroy disease. The herein described case, which is the third reported so far with c.3109G>C mutation, adds data on genotypic-phenotypic correlation of Milroy disease. The relative literature regarding the pathophysiology, molecular basis, clinical spectrum and treatment of Milroy disease is reviewed.


Lymphatic dysfunction, not aplasia, underlies Milroy disease.

May 2010

Mellor RH, Hubert CE, Stanton AW, Tate N, Akhras V, Smith A, Burnand KG, Jeffery S, Mäkinen T, Levick JR, Mortimer PS. Source Cardiac & Vascular Sciences (Dermatology), St George's Hospital Medical School, University of London, London, UK. Abstract OBJECTIVE: Milroy disease is an inherited autosomal dominant lymphoedema caused by mutations in the gene for vascular endothelial growth factor receptor-3 (VEGFR-3, also known as FLT4). The phenotype has to date been ascribed to lymphatic aplasia. We further investigated the structural and functional defects underlying the phenotype in humans.

METHODS: The skin of the swollen foot and the non-swollen forearm was examined by (i) fluorescence microlymphangiography, to quantify functional initial lymphatic density in vivo; and (ii) podoplanin and LYVE-1 immunohistochemistry of biopsies, to quantify structural lymphatic density. Leg vein function was assessed by colour Doppler duplex ultrasound.

RESULTS: Milroy patients exhibited profound (86-91%) functional failure of the initial lymphatics in the foot; the forearm was unimpaired. Dermal lymphatics were present in biopsies but density was reduced by 51-61% (foot) and 26-33% (forearm). Saphenous venous reflux was present in 9/10 individuals with VEGFR3 mutations, including two carriers.

CONCLUSION: We propose that VEGFR3 mutations in humans cause lymphoedema through a failure of tissue protein and fluid absorption. This is due to a profound functional failure of initial lymphatics and is not explained by microlymphatic hypoplasia alone. The superficial venous valve reflux indicates the dual role of VEGFR-3 in lymphatic and venous development.

Wiley Online Library

Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Oct 2006

Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken JB, Boon LM, Vikkula M.


Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Brussels, Belgium.


Mutations in the vascular endothelial growth factor receptor 3 gene, VEGFR3/FLT4, have been identified in a subset of families with hereditary lymphedema type I or Milroy disease (MIM 153100). Individuals carrying a VEGFR3 mutation exhibit congenital edema of the lower limbs, usually bilaterally and below the knees, sometimes associated with cellulitis, prominent veins, papillomatosis, upturned toenails, and hydrocele. In this study, we report the first de novo VEGFR3 mutation in a patient with sporadic congenital lymphedema. We also describe three other families with a VEGFR3 mutation. In each family, one individual had an atypical clinical presentation of hereditary lymphedema type I, whereas the others had the classical VEGFR3 mutation-caused phenotype. The atypical presentations included pre-natal pleural effusion, spontaneous resorption of lymphedema and elephantiasis. Three of the four identified mutations were novel. These data show that de novo VEGFR3 mutations may be present in patients without family history of congenital lymphedema. This has implications for follow-up care, as such individuals have nearly a 50% risk for occurrence of lymphedema in their children. Our findings also indicate that although most patients with a VEGFR3 mutation have the well-defined phenotype for hereditary lymphedema type I, there are exceptions that should be considered in genetic counseling. Because VEGFR3 mutation can cause generalized lymphatic dysfunction and can thus result in hydrops fetalis, VEGFR3 screening should be added to the investigation of cases of hydrops fetalis of an unknown etiology.

Wiley Online

External Links

Lymphedema People Related Internal Links

Lymphedema People Resources

Lymphedema Family Study

Please support this important work

Welcome to the Lymphedema Family Study at the University of Pittsburgh! The goal of this project is to identify genes responsible for primary lymphedema. It is our hope that a new understanding of the genetic basis of inherited lymphedema will provide insight into its treatment and contribute to early identification of individuals at risk. Click on the links to the left for frequently asked questions about this condition, information about the inheritance of primary lymphedema, previous investigations into the genetic aspects of lymphedema, an update of our research, and listings of our references and other lymphedema websites.

This study does not involve diagnosis or treatment of lymphedema, and it was not designed to provide any direct benefit to the participants. However, it is our hope that it will benefit many lymphedema patients in the future. If there are at least two people (including you) in your family with primary lymphedema, and you would like more information on how to become involved in the Lymphedema Family Study, please contact the coordinator of this study, Kelly Knickelbein, M.S., at the address or phone number below:

Lymphedema Family Study University of Pittsburgh Department of Human Genetics A300 Crabtree Hall, GSPH Pittsburgh, PA 15261 Phone: (412) 624-4657 or (800) 263-2152


Please be sure to include the words LYMPHEDEMA or GENETIC in your subject line.

The Lymphatic Research Foundation

The Lymphatic Research Foundation is a 501©(3) not-for profit organization whose mission is to advance research of the lymphatic system and to find the cause of and cure for lymphatic diseases, lymphedema, and related disorders.


lymphedema_gene_flt4.txt · Last modified: 2012/10/16 14:40 (external edit)