GJC2 Missense Mutations Cause Human Lymphedema

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2010; 86(6):943-8. DOI: 10.1016/j.ajhg.2010.04.010
Source: PubMed


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.

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Available from: Stephen D Meriney, Jan 30, 2014
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    • "Insufficiency of the lymphatic vascular system leads to the formation of lymphedema, a condition characterized by massive swelling of affected limbs, fibrosis, and impaired immunity [1]. In humans, mutations in VEGF-C, VEGFR3, GJC2, GJA1, KIF11, FOXC2, CCBE1, SOX18, PTPN14, and GATA2 have been found in families with inherited forms of lymphedema and cause striking defects in the development of the lymphatic vasculature [2]–[12]. These important clinical observations have fueled efforts to further identify the molecular mechanisms governing the formation of the lymphatic vasculature. "
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    ABSTRACT: Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed by lymphatic endothelial cells and has been shown to stimulate lymphangiogenesis in adult mice. However, the role VEGFR2 serves in the development of the lymphatic vascular system has not been defined. Here we use the Cre-lox system to show that the proper development of the lymphatic vasculature requires VEGFR2 expression by lymphatic endothelium. We show that Lyve-1(wt/Cre);Vegfr2(flox/flox) mice possess significantly fewer dermal lymphatic vessels than Vegfr2(flox/flox) mice. Although Lyve-1(wt/Cre);Vegfr2(flox/flox) mice exhibit lymphatic hypoplasia, the lymphatic network is functional and contains all of the key features of a normal lymphatic network (initial lymphatic vessels and valved collecting vessels surrounded by smooth muscle cells (SMCs)). We also show that Lyve-1(Cre) mice display robust Cre activity in macrophages and in blood vessels in the yolk sac, liver and lung. This activity dramatically impairs the development of blood vessels in these tissues in Lyve-1(wt/Cre);Vegfr2(flox/flox) embryos, most of which die after embryonic day14.5. Lastly, we show that inactivation of Vegfr2 in the myeloid lineage does not affect the development of the lymphatic vasculature. Therefore, the abnormal lymphatic phenotype of Lyve-1(wt/Cre);Vegfr2(flox/flox) mice is due to the deletion of Vegfr2 in the lymphatic vasculature not macrophages. Together, this work demonstrates that VEGFR2 directly promotes the expansion of the lymphatic network and further defines the molecular mechanisms controlling the development of the lymphatic vascular system.
    PLoS ONE 09/2013; 8(9):e74686. DOI:10.1371/journal.pone.0074686 · 3.23 Impact Factor
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    • "To date, only a limited number of genes are known to be involved in heritable lymphedema syndromes. Congenital isolated lymphedema can be caused by mutations in the lymphatic specific growth factor VEGFC receptor VEGFR3 [Irrthum et al., 2000; Karkkainen et al., 2000], and sometimes the lymphedema in patients with mutations in GJC2 is congenital [Ferrell et al., 2010, Ostergaard et al., 2011]. Congenital lymphedema is frequently syndromic , and causative genes have been found for the lymphedema-distichiasis syndrome (FOXC2) , hypotrichosislymphedema-telangiectasia syndrome (SOX18) , incontinentia pigmenti (IKBKG) , Noonan syndrome ( PTPN11 and other RAS-MAPK pathway genes), congenital disorder of glycosylation type 1a (PMM2) , and the choanal atresia and lymphedema syndrome (PTPN14) [Van Schaftingen and Jaeken, 1995; Fang et al., 2000; Döffinger et al., 2001; Tartaglia et al., 2001; Irrthum et al., 2003; Au et al., 2010]. "
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    ABSTRACT: The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.
    Molecular syndromology 03/2013; 4(3):107-13. DOI:10.1159/000342486
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    • "Two other Connexins, Cx43 and Cx47, were shown to be enriched in mature lymphatic valves [22, 43]. Interestingly, Cx43 deficiency in mice also led to abnormal lymphatic development, including defective valve formation [43], while GJC2 (encoding Cx47) was found to be mutated in lymphedema patients [52, 53]. These studies suggest a more general role for gap-junction-mediated signaling in the lymphatic vasculature. "
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    ABSTRACT: The efficient transport of blood and lymph relies on competent intraluminal valves that ensure unidirectional fluid flow through the vessels. In the lymphatic vessels, lack of luminal valves causes reflux of lymph and can lead to lymphedema, while dysfunction of venous valves is associated with venous hypertension, varicose veins, and thrombosis that can lead to edema and ulcerations. Despite their clinical importance, the mechanisms that regulate valve formation are poorly understood and have only recently begun to be characterized. Here, we discuss new findings regarding the development of venous and lymphatic valves that indicate the involvement of common molecular mechanisms in regulating valve formation in different vascular beds.
    Cellular and Molecular Life Sciences CMLS 08/2012; 70(6). DOI:10.1007/s00018-012-1110-6 · 5.81 Impact Factor
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