Alternatively, specific Cx47 mutations might negatively affect the expression or function of other proteins critical for lymphatic function, including other Cx isoforms that potentially interact with Cx47.18 In support of this possibility, a missense mutation in the extracellular domains of Cx47, which is associated with dominantly inherited human primary lymphedema, resulted in a 2-fold increase in the number of jugular lymph nodes in mice, and lymph reflux in mesenteric collectors37 suggestive of changes in both lymphangiogenesis and valve function. Here, GJC2 is linked to primary lymphedema.