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Extended report
MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease
  1. Monique Stoffels1,2,3,
  2. Agata Szperl4,
  3. Anna Simon1,2,3,
  4. Mihai G Netea1,2,3,
  5. Theo S Plantinga1,2,
  6. Marcel van Deuren1,2,
  7. Sylvia Kamphuis5,
  8. Helen J Lachmann6,
  9. Edwin Cuppen7,
  10. Wigard P Kloosterman7,
  11. Joost Frenkel8,
  12. Cleo C van Diemen4,
  13. Cisca Wijmenga4,
  14. Marielle van Gijn7,
  15. Jos W M van der Meer1,2,3
  1. 1Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2Nijmegen Centre for Infection, Inflammation and Immunity (N4i), Nijmegen, The Netherlands
  3. 3Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Genetics, UMC Groningen, Groningen, The Netherlands
  5. 5Sophia Children's Hospital, Erasmus UMC, Rotterdam, The Netherlands
  6. 6Division of Medicine, University College London Medical School, Royal Free Campus, National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, London, UK
  7. 7Department of Medical Genetics, UMC Utrecht, Utrecht, The Netherlands
  8. 8Department of Pediatrics, UMC Utrecht, Utrecht, The Netherlands
  1. Correspondence to Monique Stoffels, Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, 463 UMC St Radboud, PO Box 9101, Nijmegen 6500 HB, The Netherlands; m.stoffels{at}


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 1β 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.

  • Familial Mediterranean Fever
  • Fever Syndromes
  • Inflammation

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