Familial autoinflammatory diseases: genetics, pathogenesis and treatment

Stojanov, S; Kastner, Daniel L.

doi:10.1097/bor.0000174210.78449.6b

Cited by 323 publications

(234 citation statements)

References 116 publications

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“…[1][2][3] This group of diseases comprises three syndromes associated with mutations in NALP3, a key component of the inflammasome 4 : Muckle-Wells syndrome, familial cold urticaria 5 and chronic infantile neurological cutaneous and articular syndrome/ OMID, 6 as well as other syndromes like hyper-IgD, 7,8 PAPA syndrome, 9 TRAPS 10,11 and familial Mediterranean fever (FMF). 12,13 The latter is a recessively inherited disorder, in which mutations occur in the pyrin gene.…”

mentioning

confidence: 99%

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

et al. 2007

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The autoinflammatory disorders Muckle-Wells syndrome, familial cold urtecaria and chronic infantile neurological cutaneous and articular syndrome are associated with mutations in the NALP3 (Cryopyrin) gene, which is the central platform of the proinflammatory caspase-1 activating complex, named the inflammasome. In patients with another autoinflammatory disorder, familial Mediterranean fever (FMF), mutations in the SPRY domain of the Pyrin protein are frequently found. Recent evidence suggests that Pyrin associates with ASC, an inflammasome component, via its Pyrin domain, thereby halting the inflammatory response. This interaction, however, does not explain the effects of mutations of the SPRY domain found in FMF patients. Here we show that the Pyrin SPRY domain not only interacts with NALP3, but also with caspase-1 and its substrate pro-interleukin(IL)-1b. Whereas a Pyrin knockdown results in increased caspase-1 activation and IL-1b secretion, overexpression of the SPRY domain alone blocks these processes. Thus Pyrin binds to several inflammasome components thereby modulating their activity.

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confidence: 99%

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

et al. 2007

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“…These latter compounds are involved in the post-translational isoprenylation (farnesylation or geranylation) of several important intracellular signaling molecules, including the Ras, Rho/Rac, and Rab families of small guanosine triphosphate-binding proteins. In an in vitro system, accentuated IL-1β secretion by leukocytes from HIDS patients can be reversed by the addition of farnesol or geranyl-geraniol, leading support to the second hypothesis (Stojanov and Kastner, 2005). Both the isoprenoid deficiency and the mevalonate accumulation hypotheses predict symptoms worsening with decreased mevalonate kinase enzymatic activity (Stojanov and Kastner, 2005).…”

Section: Discussionmentioning

confidence: 94%

“…In an in vitro system, accentuated IL-1β secretion by leukocytes from HIDS patients can be reversed by the addition of farnesol or geranyl-geraniol, leading support to the second hypothesis (Stojanov and Kastner, 2005). Both the isoprenoid deficiency and the mevalonate accumulation hypotheses predict symptoms worsening with decreased mevalonate kinase enzymatic activity (Stojanov and Kastner, 2005). Accordingly, the level of mevalonic acid excreted in urine is admitted to be of diagnostic value.…”

Section: Discussionmentioning

confidence: 98%

“…How mevalonate kinase deficiency leads to inflammation is incompletely understood, with two major hypotheses for the disease's pathogenesis: the accumulation of products upstream of the step catalyzed by the mevalonate kinase enzyme, such as mevalonic acid, or the marked reduction of products downstream this step, including cholesterol or isoprenoids (Stojanov and Kastner, 2005). These latter compounds are involved in the post-translational isoprenylation (farnesylation or geranylation) of several important intracellular signaling molecules, including the Ras, Rho/Rac, and Rab families of small guanosine triphosphate-binding proteins.…”

Section: Discussionmentioning

confidence: 99%

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Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype

Santos¹,

Aróstegui²,

Brito³

et al. 2014

Gene

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Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; MIM# 260920) is a rare recessively-inherited autoinflammatory condition caused by mutations in the MVK gene, which encodes for mevalonate kinase, an essential enzyme in the isoprenoid pathway. HIDS is clinically characterized by recurrent episodes of fever and inflammation. Here we report on the case of a 2 year-old Portuguese boy with recurrent episodes of fever, malaise, massive cervical lymphadenopathy and hepatosplenomegaly since the age of 12 months. Rash, arthralgia, abdominal pain and diarrhea were also seen occasionally. During attacks a vigorous acute-phase response was detected, including elevated erythrocyte sedimentation rate, C-reactive protein, serum amyloid A and leukocytosis. Clinical and laboratory improvement was seen between attacks. Despite normal serum IgD level, HIDS was clinically suspected. Mutational MVK analysis revealed the homozygous genotype with the novel p.Arg277Gly (p.R277G) mutation, while the healthy non-consanguineous parents were heterozygous. Short nonsteroidal anti-inflammatory drugs and corticosteroid courses were given during attacks with poor benefits, whereas anakinra showed positive responses only at high doses. The p.R277G mutation here described is a novel missense MVK mutation, and it has been detected in this case with a severe HIDS phenotype. Further studies are needed to evaluate a co-relation genotype, enzyme activity and phenotype, and to define the best therapeutic strategies.

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“…68 Similar analyses have been performed in populations defined by the mutations in genes that are responsible for the hereditary inflammatory diseases FMF, Familial Cold Urticaria (FCAS), Muckle-Wells Syndrome (MWS), Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF-receptor associated periodic syndromes (TRAPS), Neonatal-onset inflammatory disease/ chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA) and Pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). [76][77][78][79] All of these are characterized by recurrent febrile episodes with various constellations of clinical features. AA amyloidosis is common in FMF, rare in HIDS, uncommon in FCAS, present in about 10% of cases of TRAPS, and 25% of MWS.…”

Section: Amyloidoses Derived From Molecules Involved In Immune Functionmentioning

confidence: 99%

The genetics of the amyloidoses: interactions with immunity and inflammation

Buxbaum

2006

Genes Immun

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Historically, the amyloidoses have been associated with inflammation and the immune response. From Virchow's original description in human pathologic inflammatory states through their identification in horses used to produce antitoxin to their frequent occurrence in the course of multiple myeloma and a somewhat abortive designation as 'gammaloid', the disorders were felt to have an inflammatory origin. These presumptive associations antedated the availability of a reliable method for tissue extraction that would allow chemical analysis of the major deposited molecules. With the identification of the multiple precursors and the realization that most were not intrinsic elements of immune/inflammatory pathways, the investigative emphasis shifted to the analysis of the biophysical events involved in aggregation and fibril formation. As more in vivo models and better tools for examination of tissues have become available, it appears as if inflammation may participate as both a response to, and an amplifier of, the effects of the fibrillar aggregates. Hence, while only a limited number of amyloid protein precursors are involved in immunity and inflammation per se, host defense, in its broadest sense, is likely to be involved in the clinically relevant amyloidoses. Further it now appears that harnessing the immune respone in an appropriate fashion may be able to play a role in treatment.

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Familial autoinflammatory diseases: genetics, pathogenesis and treatment

Cited by 323 publications

References 116 publications

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1β processing

Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype

The genetics of the amyloidoses: interactions with immunity and inflammation

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