Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genetics of monogenic autoinflammatory diseases: past successes, future challenges


The term autoinflammation was initially coined to distinguish disorders characterized by recurrent episodes of inflammation in the absence of high-titer autoantibodies and antigen-specific T cells from the more common autoimmune diseases. Although this concept originally applied to monogenic hereditary recurrent fevers, it has expanded over time to include polygenic (complex) autoinflammatory diseases. Understanding of the pathogenesis of autoinflammatory diseases has grown rapidly in the past decade owing to advances in genome research and technology. Genome-wide linkage analysis, positional cloning, homozygosity mapping and candidate gene screening have led to the identification of mutations in 12 genes that are associated with monogenic diseases. Genome-wide association studies have begun to elucidate the molecular basis of complex autoinflammatory diseases. The discovery of disease-causing genetic variants has defined autoinflammation as disorder within the innate immune system, implicating IL-1 as a master cytokine, and has led to a breakthrough in therapy, with IL-1 inhibitors producing rapid and sustained amelioration of symptoms. Despite major advances, however, a substantial number of patients have no mutations in the known autoinflammatory genes. The challenge now is to find the undiscovered genes, considering that most cases are sporadic or occur within small families. New approaches and tools such as next-generation sequencing are discussed.

Key Points

  • A new nosology, autoinflammation, has been proposed to distinguish inherited diseases of the innate immune system from chronic inflammatory diseases that are mediated by the adaptive immune system

  • Most causal variants associated with systemic autoinflammatory diseases are missense nucleotide changes, a possible explanation for the intermittent nature of the inflammatory symptoms characteristic of these diseases

  • Mutations in the same protein have been associated with different phenotypes in human disease, and phenotypes associated with disease-causing mutations vary in animal models and human disease

  • Animal studies suggest that most causal variants of autoinflammatory diseases seem to be gain-of-function mutations, regardless of the mode of disease inheritance in humans

  • Many of the affected genes are directly or indirectly involved in the regulation of the IL-1 cytokine signaling pathway

  • Molecular insights have provided the basis for new therapeutic interventions that have had an immediate and dramatic impact on the treatment of autoinflammatory disorders

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Schematic representation of recessively inherited FMF-associated mutations in the MEFV gene.
Figure 2: Schematic representation of mutations in MVK that have been identified in patients presenting with MA or HIDS.
Figure 3: Mechanisms of autoinflammatory diseases mediated by IL-1β and IL-10.
Figure 4: Schematic representation of mutations in the TNFR1 protein that are associated with TRAPS.
Figure 5: Schematic representation of dominantly inherited NLRP3 mutations in patients with CAPS.


  1. 1

    McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Galon, J., Aksentijevich, I., McDermott, M. F., O'Shea, J. J. & Kastner, D. L. TNFRSF1A mutations and autoinflammatory syndromes. Curr. Opin. Immunol. 12, 479–486 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).

    CAS  Article  Google Scholar 

  4. 4

    The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

    Article  Google Scholar 

  5. 5

    French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).

  6. 6

    Drenth, J. P. et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat. Genet. 22, 178–181 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Houten, S. M. et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22, 175–177 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).

    CAS  Article  Google Scholar 

  9. 9

    Ferguson, P. J. et al. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J. Med. Genet. 42, 551–557 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Aksentijevich, I. et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360, 2426–2437 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Reddy, S. et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J. Med. 360, 2438–2444 (2009).

    CAS  Article  Google Scholar 

  12. 12

    Agarwal, A. K. et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87, 866–872 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Jeru, I. et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc. Natl Acad. Sci. USA 105, 1614–1619 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Remmers, E. F. et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat. Genet. 42, 698–702 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Mizuki, N. et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat. Genet. 42, 703–706 (2010).

    CAS  Article  Google Scholar 

  16. 16

    van der Hilst, J. C. et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87, 301–310 (2008).

    CAS  Article  Google Scholar 

  17. 17

    Samuels, J. et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 77, 268–297 (1998).

    CAS  Article  Google Scholar 

  18. 18

    Naruto, T. et al. Hyper-IgD syndrome with novel mutation in a Japanese girl. Mod. Rheumatol. 19, 96–99 (2009).

    Article  Google Scholar 

  19. 19

    Nisole, S., Stoye, J. P. & Saib, A. TRIM family proteins: retroviral restriction and antiviral defence. Nat. Rev. Microbiol. 3, 799–808 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Touitou, I. et al. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum. Mutat. 24, 194–198 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Institut de genetique humaine. Infevers: an online database for autoinflammatory mutations [online], (2010).

  22. 22

    Touitou, I. et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis. Rheum. 56, 1706–1712 (2007).

    Article  Google Scholar 

  23. 23

    Grateau, G. et al. Amyloidosis and auto-inflammatory syndromes. Curr. Drug Targets Inflamm. Allergy 4, 57–65 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Ben-Chetrit, E., Lerer, I., Malamud, E., Domingo, C. & Abeliovich, D. The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant? Hum. Mutat. 15, 385–386 (2000).

    CAS  Article  Google Scholar 

  25. 25

    Ryan, J. G. et al. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann. Rheum. Dis. 69, 1383–1388 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Marek-Yagel, D., Bar-Joseph, I., Pras, E. & Berkun, Y. Is E148Q a benign polymorphism or a disease-causing mutation? J. Rheumatol. 36, 2372 (2009).

    Article  Google Scholar 

  27. 27

    Gershoni-Baruch, R., Brik, R., Shinawi, M. & Livneh, A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur. J. Hum. Genet. 10, 145–149 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Masters, S. L. et al. The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat. Struct. Mol. Biol. 13, 77–84 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Woo, J. S., Suh, H. Y., Park, S. Y. & Oh, B. H. Structural basis for protein recognition by B30.2/SPRY domains. Mol. Cell 24, 967–976 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Chae, J. J. et al. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 34, 755–768 (2011).

    CAS  Article  Google Scholar 

  31. 31

    Marek-Yagel, D. et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 60, 1862–1866 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Bootym M. G. et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 60, 1851–1861 (2009).

    Article  Google Scholar 

  33. 33

    Mandey, S. H., Schneiders, M. S., Koster, J. & Waterham, H. R. Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum. Mutat. 27, 796–802 (2006).

    CAS  Article  Google Scholar 

  34. 34

    Cuisset, L. et al. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur. J. Hum. Genet. 9, 260–266 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Houten, S. M., van Woerden, C. S., Wijburg, F. A., Wanders, R. J. & Waterham, H. R. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with hyper-IgD and periodic fever syndrome, in the Netherlands. Eur. J. Hum. Genet. 11, 196–200 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Simon, A., Mariman, E. C., van der Meer, J. W. & Drenth, J. P. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am. J. Med. 114, 148–152 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Frenkel, J. et al. Lack of isoprenoid products raises ex vivo interleukin-1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum. 46, 2794–2803 (2002).

    CAS  Article  Google Scholar 

  38. 38

    Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  Article  Google Scholar 

  39. 39

    Hull, K. M. et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 81, 349–368 (2002).

    CAS  Article  Google Scholar 

  40. 40

    Simon, A. et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc. Natl Acad. Sci. USA 107, 9801–9806 (2010).

    CAS  Article  Google Scholar 

  41. 41

    Pelagatti, M. A. et al. Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. Arthritis Rheum. 63, 1141–1150 (2011).

    CAS  Article  Google Scholar 

  42. 42

    Ravet, N. et al. Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann. Rheum. Dis. 65, 1158–1162 (2006).

    CAS  Article  Google Scholar 

  43. 43

    Dowds, T. A., Masumoto, J., Zhu, L., Inohara, N. & Nunez, G. Cryopyrin-induced interleukin 1β secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. J. Biol. Chem. 279, 21924–21928 (2004).

    CAS  Article  Google Scholar 

  44. 44

    Yu, J. W. et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ. 13, 236–249 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Hawkins, P. N., Bybee, A., Aganna, E. & McDermott, M. F. Response to anakinra in a de novo case of neonatal-onset multisystem inflammatory disease. Arthritis Rheum. 50, 2708–2709 (2004).

    Article  Google Scholar 

  46. 46

    Goldbach-Mansky, R. et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N. Engl. J. Med 355, 581–592 (2006).

    CAS  Article  Google Scholar 

  47. 47

    Aksentijevich, I. et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 56, 1273–1285 (2007).

    CAS  Article  Google Scholar 

  48. 48

    Hawkins, P. N., Lachmann, H. J., Aganna, E. & McDermott, M. F. Spectrum of clinical features in Muckle–Wells syndrome and response to anakinra. Arthritis Rheum. 50, 607–612 (2004).

    CAS  Article  Google Scholar 

  49. 49

    Porksen, G. et al. Periodic fever, mild arthralgias, and reversible moderate and severe organ inflammation associated with the V198M mutation in the CIAS1 gene in three German patients—-expanding phenotype of CIAS1 related autoinflammatory syndrome. Eur. J. Haematol. 73, 123–127 (2004).

    Article  Google Scholar 

  50. 50

    Wise, C. A. et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol. Genet. 11, 961–969 (2002).

    CAS  Article  Google Scholar 

  51. 51

    Shoham, N. G. et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc. Natl Acad. Sci. USA 100, 13501–13506 (2003).

    CAS  Article  Google Scholar 

  52. 52

    Grosse, J. et al. Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease. Blood 107, 3350–3358 (2006).

    CAS  Article  Google Scholar 

  53. 53

    Chitu, V. et al. Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice. Blood 114, 2497–2505 (2009).

    CAS  Article  Google Scholar 

  54. 54

    Hurtado-Nedelec, M. et al. Genetic susceptibility factors in a cohort of 38 patients with SAPHO syndrome: a study of PSTPIP2, NOD2, and LPIN2 genes. J. Rheumatol. 37, 401–409 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Miceli-Richard, C. et al. CARD15 mutations in Blau syndrome. Nat. Genet. 29, 19–20 (2001).

    CAS  Article  Google Scholar 

  56. 56

    Kanazawa, N. et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-κB activation: common genetic etiology with Blau syndrome. Blood 105, 1195–1197 (2005).

    CAS  Article  Google Scholar 

  57. 57

    Albrecht, M., Lengauer, T. & Schreiber, S. Disease-associated variants in PYPAF1 and NOD2 result in similar alterations of conserved sequence. Bioinformatics 19, 2171–2175 (2003).

    CAS  Article  Google Scholar 

  58. 58

    Borghini, S. et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63, 830–839 (2011).

    CAS  Article  Google Scholar 

  59. 59

    Green, E. D. & Guyer, M. S. Charting a course for genomic medicine from base pairs to bedside. Nature 470, 204–213 (2011).

    CAS  Article  Google Scholar 

  60. 60

    The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 28, 1061–1073 (2010).

  61. 61

    Feldmann, J. et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am. J. Hum. Genet. 71, 198–203 (2002).

    CAS  Article  Google Scholar 

  62. 62

    Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348 (2002).

    CAS  Article  Google Scholar 

  63. 63

    Garg, A. et al. An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J. Clin. Endocrinol. Metab. 95, E58–E63 (2010).

    Article  Google Scholar 

  64. 64

    Chan, F. K., Chun, H. J., Zheng, L., Siegel, R. M., Bui, K. L. & Lenardo, M. J. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).

    CAS  Article  Google Scholar 

  65. 65

    Banner, D.W. et al. Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: implications for TNF receptor activation. Cell 73, 431–445 (1993).

    CAS  Article  Google Scholar 

  66. 66

    Saito, M. et al. Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood 111, 2132–2141 (2008).

    CAS  Article  Google Scholar 

Download references

Author information




I. Aksentijevich researched data for the article, and I. Aksentijevich and D. L. Kastner contributed equally to discussing content, writing the article, and reviewing/editing of the manuscript before submission.

Corresponding author

Correspondence to Ivona Aksentijevich.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Aksentijevich, I., Kastner, D. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 7, 469–478 (2011).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing