Related Terms: connexin 47, hereditary lymphedema, primary lymphedema, secondary lymphedema, surgery, chemotherapy, radiation, cancer, lymphedema genes, Gap Junction Proteins, Connexin32, Connexin37, Connexin43, lymphatic valve development, lymphatic disorders, chylothorax, Cx47, Cx30, Cx43
The research continues on the genetic causes of lymphedema in hopes of finding not only a treatment, but a cure and even prevention through possible genetic therapy or stem cell treatment.
Not only are specific gene being targeted and identified, but we are gaining more understanding of how the proteins encoded within these genes function and how they affect lymphatic development.
It is a group of homologous proteins which form the intermembrane channels of GAP JUNCTIONS. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of membrane proteins forming intermembrane channels of gap junctions.
Other names: Gap Junction Proteins; Proteins, Gap Junction; Protein, Gap Junction; Junction Proteins, Gap; Junction Protein, Gap; Gap Junction Protein; Gap Junction Proteins
The “gap junction” is a specialized intercellular connection between a multitude of animal types. It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells.
For further explanation of gap junction, please follow the link:
Med Terms defines Gap junction: An organized collections of protein channels in cellmembranes that allows ions and small molecules to pass between adjacent cells. The protein channels that make up gap junctions consist of two connexons. One connexon resides in the membrane of one cell. It aligns and joins the connexon of the neighboring cell, forming a continuous aqueous pathway by which ions and small molecules can freely pass (passively) from one cell to the other.
Each connexon consist of six subunits called connexins. The connexin genes have been highly conserved during evolution. In some cells the connexons are formed of six identical connexins or of some combination of two different connexins.
Gap junctions exist in almost all cell types., some exceptions being skeletal muscle, red blood cells and circulating blood lymphocytes. The size and number of gap junctions per cell can change, depending on such factors as the point in the cell cycle and exposure of the cell to environmental stress.
Gap junctions are essential for many physiological processes, such as the coordinated depolarization of cardiac muscle, proper embryonic development, and the conducted response in microvasculature. For this reason, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.
Finegold D, Baty C, Knickelbein K, Perschke S, Noon S, Campbell D, Karlsson J, Huang D, Kimak M, Lawrence E,Feingold E, Meriney S, Brufsky AM, Ferrell R.
pediatrics/human genetics, university of pittsburgh.
PURPOSE: Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied.
EXPERIMENTAL DESIGN: To determine if women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case - control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program (UPMC Cancer Ctr) between 2000-2010.Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations.
RESULTS: Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis, and provide evidence that altered gap junction function leads to lymphedema.
CONCLUSIONS: Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk 1) raises the potential for early detection and intervention for a high risk group, and 2) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin modifying drugs.
Kanady JD, Dellinger MT, Munger SJ, Witte MH, Simon AM. Source Department of Physiology, University of Arizona, Tucson, AZ 85724, USA. email@example.com
Intraluminal valves are required for the proper function of lymphatic collecting vessels and large lymphatic trunks like the thoracic duct. Despite recent progress in the study of lymphvasculogenesis and lymphangiogenesis, the molecular mechanisms controlling the morphogenesis of lymphatic valves remain poorly understood. Here, we report that gap junction proteins, or connexins (Cxs), are required for lymphatic valvulogenesis. Cx37 and Cx43 are expressed early in mouse lymphatic development in the jugular lymph sacs, and later in development these Cxs become enriched and differentially expressed by lymphatic endothelial cells on the upstream and downstream sides of the valves. Specific deficiencies of Cx37 and Cx43 alone or in combination result in defective valve formation in lymphatic collecting vessels, lymphedema, and chylothorax. We also show that Cx37 regulates jugular lymph sac size and that both Cx37 and Cx43 are required for normal thoracic duct development, including valve formation. Another Cx family member, Cx47, whose human analog is mutated in some families with lymphedema, is also highly enriched in a subset of endothelial cells in lymphatic valves. Mechanistically, we present data from Foxc2-/- embryos suggesting that Cx37 may be a target of regulation by Foxc2, a transcription factor that is mutated in human lymphedema-distichiasis syndrome. These results show that at least three Cxs are expressed in the developing lymphatic vasculature and, when defective, are associated with clinically manifest lymphatic disorders in mice and man.
Ferrell RE, Baty CJ, Kimak MA, Karlsson JM, Lawrence EC, Franke-Snyder M, Meriney SD, Feingold E, Finegold DN. Source Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Lymphedema is the clinical manifestation of defects in lymphatic structure or function. Mutations identified in genes regulating lymphatic development result in inherited lymphedema. No mutations have yet been identified in genes mediating lymphatic function that result in inherited lymphedema. Survey microarray studies comparing lymphatic and blood endothelial cells identified expression of several connexins in lymphatic endothelial cells. Additionally, gap junctions are implicated in maintaining lymphatic flow. By sequencing GJA1, GJA4, and GJC2 in a group of families with dominantly inherited lymphedema, we identified six probands with unique missense mutations in GJC2 (encoding connexin [Cx] 47). Two larger families cosegregate lymphedema and GJC2 mutation (LOD score = 6.5). We hypothesize that missense mutations in GJC2 alter gap junction function and disrupt lymphatic flow. Until now, GJC2 mutations were only thought to cause dysmyelination, with primary expression of Cx47 limited to the central nervous system. The identification of GJC2 mutations as a cause of primary lymphedema raises the possibility of novel gap-junction-modifying agents as potential therapy for some forms of lymphedema.
Full Text Article: PubMed Central
Sargiannidou I, Markoullis K, Kleopa KA.
Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Key words: Connexin32, Connexin47, Schwann cells, Oligodendrocytes, X-linked Charcot-Marie-Tooth Disease, Pelizaeus-Merzbacher-like disease
There is an emerging group of neurological disorders that result from genetic mutations affecting gap junction proteins in myelinating cells. The X-linked form of Charcot Marie Tooth disease (CMT1X) is caused by numerous mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32), which is expressed in both Schwann cells in the PNS and oligodendrocytes in the CNS. Patients with CMT1X present mainly with a progressive peripheral neuropathy, showing mixed axonal and demyelinating features. In many cases there is also clinical or subclinical involvement of the CNS with acute or chronic phenotypes of encephalopathy. Furthermore, mutations in the GJA12/GJC2 gene encoding the gap junction protein Cx47, which is expressed in oligodendrocytes, have been identified in families with progressive leukodystrophy, known as Pelizaeus-Merzbacher-like disease, as well as in patients with hereditary spastic paraplegia. Recent studies have provided insights into the pattern of gap junction protein expression and function in CNS and PNS myelinating cells. Furthermore, in vitro and in vivo disease models have clarified some of the molecular and cellular mechanisms underlying these disorders. Here we provide an overview of the clinical, genetic, and neurobiological aspects of gap junction disorders affecting the nervous system.
Full Text Article: Histology and Histopathology
Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning. 2005
This is perhaps one of the most important centers for us as lymphedema patients. The pace of genetic research is exploding and it will be through this type of research that we will come to know and understand:
1.) What causes lymphedema - the genetics involved.
2.) The path to a genetic cure.
3.) The ability to provide treatment.
How many times have we said, “we wished someone could find out what causes lymphedema?” Countless, countless times. The serious problem we face now is that due to the economy funding programs for this research has almost dried up and the program in very much in danger of being shutdown early next year.
Friends, we absolutely must save this program. Should it be closed, we would loose just about our only hope of a cure. We would also loose some of the most committed doctors, and support staff.
Please visit the site and go through their information. Support them as much as it is possible.