GJC2 Missense Mutations Cause Human Lymphedema

Abstract

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.

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Recently, two more genes (GJC2 and CCBE1) were identified to be causally associated with lymphedema. The GJC2 gene encodes connexin 47, an intercellular gap junction protein, and mutations in the protein were postulated to cause impaired gap junction activities and result in defective lymphatic flow (Ferrell et al 2010). CCBE1 has been shown to play a role in lymphatic sprouting during zebrafish development, and mutations in CCBE1 were found in patients with Hennekam lymphangiectasia -lymphedema syndrome (Alders et al 2009;Hogan et al 2009).…”

Peripheral lymphangiogenesis in mice depends on ectodermal connexin-26 (Gjb2)

“…The authors conclude that Cx26 seems to enhance metastasis, probably by promoting invasion of the lymphatic vessels. Very recently, mutations in GJC2 (Cx47), another member of the connexin family, have been reported to cause primary lymphedema in humans (Ferrell et al, 2010;Ostergaard et al, 2011). With this in mind, it appears promising to further analyze connexin protein expression and function during development and maintenance of the lymphatic vessel system in mice and humans.…”

“…Recently it has been shown that certain mutations in the human gap junction protein Cx47 can cause 2807 Cx26 in peripheral lymphangiogenesis inherited human lymphedema (Ferrell et al, 2010;Ostergaard et al, 2011). In this study we investigated the essential role of ectodermally expressed Cx26 for peripheral lymphangiogenesis in mice.…”

Diabetic foot ulcers in conjunction with lower limb lymphedema: pathophysiology and treatment procedures

“…43 Data suggest that coordinated function of gap junctions is needed to mediate the propagation of spontaneous contractions in the lymphatic vasculature. 44 Although these in vivo studies have demonstrated the effect of deletion of connexin, it is still unknown if the changes in expression of connexin seen in chronic wounds affect lymphangiogenesis.…”