Open AccessAncient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis
Author(s) -
Yong Hwan Park,
Elaine F. Remmers,
Wonyong Lee,
Amanda K. Ombrello,
Lawton K. Chung,
Shilei Zhao,
Deborah L. Stone,
Maya I. Ivanov,
Nicole A. Loeven,
Karyl S. Barron,
Patrycja Hoffmann,
Michele Nehrebecky,
Yeliz Z. AkkayaUlum,
Erdal Sağ,
Banu BalcıPeynircioğlu,
Ivona Aksentijevich,
Ahmet Gül,
Charles N. Rotimi,
Hua Chen,
James B. Bliska,
Seza Özen,
Daniel L. Kastner,
Daniel Shriner,
Jae Jin Chae
Publication year - 2020
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-020-0705-6
Subject(s) - pyrin domain , familial mediterranean fever , mefv , biology , yersinia pestis , genetics , inflammasome , mutant , mutation , microbiology and biotechnology , virulence , gene , gene mutation , medicine , disease , receptor , pathology
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)-1β suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1β 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.