| First Author | Park YH | Year | 2020 |
| Journal | Nat Immunol | Volume | 21 |
| Issue | 8 | Pages | 857-867 |
| PubMed ID | 32601469 | Mgi Jnum | J:306322 |
| Mgi Id | MGI:6706608 | Doi | 10.1038/s41590-020-0705-6 |
| Citation | Park YH, et al. (2020) Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis. Nat Immunol 21(8):857-867 |
| abstractText | Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1beta suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1beta specifically in response to Y. pestis. Y. pestis-infected Mefv(M680I/M680I) FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis. |
