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Park, Yong Hwan
유전체 항상성 연구단
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Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis

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Title
Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis
Author(s)
Park, Yong Hwan; Remmers E.F.; Lee W.; Ombrello A.K.; Chung L.K.; Shilei Z.; Stone D.L.; Ivanov M.I.; Loeven N.A.; Barron K.S.; Hoffmann P.; Nehrebecky M.; Akkaya-Ulum Y.Z.; Sag E.; Balci-Peynircioglu B.; Aksentijevich I.; Gul A.; Rotimi C.N.; Chen H.; Bliska J.B.; Ozen S.; Kastner D.L.; Shriner D.; Chae J.J.
Subject
RECENT POSITIVE SELECTION, ; YERSINIA-PESTIS, ; HOST KINASES, ; HUMAN GENOME, ; PROTEIN, ; YOPM, ; ACTIVATION, ; CARRIER, ; MEFV, ; GENE
Publication Date
2020-06
Journal
NATURE IMMUNOLOGY, v.21, no.8, pp.857 - 867
Publisher
NATURE PUBLISHING GROUP
Abstract
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.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 MefvM680I/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
URI
https://pr.ibs.re.kr/handle/8788114/7821
DOI
10.1038/s41590-020-0705-6
ISSN
1529-2908
Appears in Collections:
Center for Genomic Integrity(유전체 항상성 연구단) > 1. Journal Papers (저널논문)
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