Recent advances in the molecular pathogenesis of hereditary recurrent fevers

Curr Opin Allergy Clin Immunol. 2006 Dec;6(6):428-33. doi: 10.1097/ACI.0b013e3280109b57.


Purpose of review: To discuss recent developments in the molecular basis of several hereditary recurrent fever syndromes, specifically the cryopyrin-associated periodic syndromes, familial Mediterranean fever and the tumor necrosis factor receptor associated periodic syndrome.

Recent findings: Mutations of CIAS1, the gene encoding cryopyrin/NALP3, lead to a spectrum of disease states termed the cryopyrinopathies. Recently, cryopyrin-deficient mice have been used to show that the protein is a key regulator of interleukin-1beta production that functions by recognizing stimuli such as bacterial RNA and infectious agents. Tumor necrosis factor receptor-associated periodic syndrome was initially thought to be caused by deficient metalloprotease-induced tumor necrosis factor receptor shedding, however new findings suggest that mutations in this receptor may result in inappropriate protein folding, leading to a host of other functional abnormalities that may cause inflammatory disease. Finally, data are emerging that address the possible function of the C-terminal B30.2 domain of pyrin, the familial Mediterranean fever protein. This motif has recently been shown to interact with and inhibit caspase-1, and the modeled structure of this complex highlights how mutations may affect the binding interface.

Summary: Recent reports have advanced our understanding of the structural and functional biology underlying the hereditary recurrent fevers, and are beginning to suggest possible mechanisms by which specific mutations cause disease.

Publication types

  • Review

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / immunology
  • Animals
  • Carrier Proteins / genetics*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / immunology
  • Familial Mediterranean Fever / genetics*
  • Familial Mediterranean Fever / immunology
  • Familial Mediterranean Fever / pathology
  • Humans
  • Metalloproteases / deficiency*
  • Metalloproteases / immunology
  • Mutation / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Pyrin
  • Receptors, Tumor Necrosis Factor / genetics*
  • Receptors, Tumor Necrosis Factor / immunology


  • Carrier Proteins
  • Cytoskeletal Proteins
  • MEFV protein, human
  • Mefv protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Pyrin
  • Receptors, Tumor Necrosis Factor
  • Metalloproteases
  • Caspase 1