Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism

Matteo Fumagalli, Stephane M. Camus, Yoan Diekmann, Alice Burke, Marine D. Camus, Paul J. Norman, Agnel Joseph, Laurent Abi-Rached, Andrea Benazzo, Rita Rasteiro, Iain Mathieson, Maya Topf, Peter Parham, Mark G. Thomas, Frances M. Brodsky

Research output: Contribution to journalArticle (Academic Journal)peer-review

13 Citations (Scopus)
176 Downloads (Pure)


CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22's role in metabolism and have potential to differentially influence the human insulin response.

Original languageEnglish
Article numbere41517
Number of pages29
Publication statusPublished - 4 Jun 2019


  • cell biology
  • evolutionary biology
  • evolutionary selection
  • human
  • insulin response
  • membrane traffic


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