Guest post by Robert Erickson (ASHG poster: Wed Oct 17th, 2:00pm – 3:00pm)
Human dominant, gain-of-function mutations in connexin 47 can cause lymphedema but are not always penetrant. We sought to better understand the causes of variable penetrance and expressivity of one such mutant, R260C, by using CRISPR technology to create this mutant in mice of different genetic backgrounds. Only mice homozygous for the mutation on the C57BL/6J genetic background showed a lymphatic phenotype. As with other mouse models for human lymphedema-causing mutations, overt limb swelling was not seen. Instead, there were increased numbers and size of lymph nodes, with increased lobulation. In addition, there was abnormal chylous reflux and increased lymphatic branching in the ears. Mice on genetic backgrounds which were 75% 129/J or A/J did not show abnormalities even when homozygous for the mutation. These results suggest that modifying genes are important for the e expression of human CX47 gain-of-function mutations.