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.

Figure 1

Pedigrees of the Two Linked Families Pedigrees of the two linked families showing current age or age at death, cosegregation of GJC2 missense mutation with lymphedema, age at onset of lymphedema of the leg and/or hand, and other phenotypic features. Family 168, R260C, and family 135, S48L, are shown. Filled shapes indicate affected individuals with lymphedema. LOD = 6.5. Arrows indicates the probands.

Figure 2

Schematic Drawing of Connexin 47 Protein Locating Lymphedema-Associated Amino Acid Substitutions Domain break points and sequence are as described by Uhlenberg et al. and http://www.uniprot.org/uniprot/Q5T442.

Figure 3

Amino Acid Alignment of Cx47 from Different Species Tan indicates intracellular domains; green indicates transmembrane domains; white indicates extracellular domains. Red dots represent the positions of amino acids altered in lymphedema families.