MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease

Monique Stoffels*, Agata Szperl, Anna Simon, Mihai G. Netea, Theo S. Plantinga, Marcel van Deuren, Sylvia Kamphuis, Helen J. Lachmann, Edwin Cuppen, Wigard P. Kloosterman, Joost Frenkel, Cleo C. van Diemen, Cisca Wijmenga, Marielle van Gijn, Jos W. M. van der Meer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Objectives Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome. We aimed to unravel the genetic cause of the symptoms.

Methods Whole exome sequencing was used to screen for novel sequence variants, which were validated by direct Sanger sequencing. Ex vivo stimulation with peripheral blood mononuclear cells was performed to study the functional consequences of the mutation. mRNA and cytokine levels were measured by quantitative PCR and ELISA, respectively.

Results Whole exome sequencing revealed a novel missense sequence variant, not seen in around 6800 controls, mapping to exon 8 of the MEFV gene (c.1730C>A; p.T577N), co-segregating perfectly with disease in this family. Other mutations at the same amino acid (c.1730C>G; p.T577S and c.1729A>T; p.T577S) were found in a family of Turkish descent, with autosomal dominant inheritance of familial Mediterranean fever (FMF)-like phenotype, and a Dutch patient, respectively. Moreover, a mutation (c.1729A>G; p.T577A) was detected in two Dutch siblings, who had episodes of inflammation of varying severity not resembling FMF. Peripheral blood mononuclear cells from one patient of the index family showed increased basal interleukin 1 beta mRNA levels and cytokine responses after lipopolysaccharide stimulation. Responses normalised with colchicine treatment.

Conclusions Heterozygous mutations at amino acid position 577 of pyrin can induce an autosomal dominant autoinflammatory syndrome. This suggests that T577, located in front of the C-terminal B30.2/SPRY domain, is crucial for pyrin function.

Original languageEnglish
Pages (from-to)455-461
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume73
Issue number2
DOIs
Publication statusPublished - Feb-2014

Keywords

  • FAMILIAL MEDITERRANEAN FEVER
  • NF-KAPPA-B
  • MISSENSE MUTATIONS
  • B30.2 DOMAIN
  • PROTEIN
  • GENE
  • EXPRESSION
  • IL-1-BETA
  • PHENOTYPE
  • CASPASE-1

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