The Changing Concepts Regarding the Mediterranean Fever Gene: Toward a Spectrum of Pyrin-Associated Autoinflammatory Diseases with Variable Heredity

Boursier, Guilaine; Hentgen, Véronique; Sarrabay, Guillaume; Koné‐Paut, Isabelle; Touitou, Isabelle

doi:10.1016/j.jpeds.2019.02.039

Cited by 16 publications

(6 citation statements)

References 39 publications

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“…Here, we identified that different mutations affecting the CHS domain differentially affect the pyrin inflammasome response and potentially the clinical presentation of the patients. Thus, our study strengthens the concept of a spectrum of MEFV mutations, affecting differently the regulation mechanisms of the pyrin protein and leading to Pyrin-Associated Autoinflammatory Diseases [ 40 ] with varying degrees of severity.…”

Section: Discussionsupporting

confidence: 84%

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

et al. 2023

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Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disorder. FMF is caused by mutations in the MEFV gene, encoding pyrin, an inflammasome sensor. The best characterized pathogenic mutations associated with FMF cluster in exon 10. Yet, mutations have been described along the whole MEFV coding sequence. Exon 10 encodes the B30.2 domain of the pyrin protein, but the function of this human-specific domain remains unclear. Pyrin is an inflammasome sensor detecting RhoA GTPase inhibition following exposure to bacterial toxins such as TcdA. Here, we demonstrate that the B30.2 domain is dispensable for pyrin inflammasome activation in response to this toxin. Deletion of the B30.2 domain mimics the most typical FMF-associated mutation and confers spontaneous inflammasome activation in response to pyrin dephosphorylation. Our results indicate that the B30.2 domain is a negative regulator of the pyrin inflammasome that acts independently from and downstream of pyrin dephosphorylation. In addition, we identify the central helical scaffold (CHS) domain of pyrin, which lies immediately upstream of the B30.2 domain as a second regulatory domain. Mutations affecting the CHS domain mimic pathogenic mutations in the B30.2 domain and render the pyrin inflammasome activation under the sole control of the dephosphorylation. In addition, specific mutations in the CHS domain strongly increase the cell susceptibility to steroid catabolites, recently described to activate pyrin, in both a cell line model and in monocytes from genotype-selected FMF patients. Taken together, our work reveals the existence of two distinct regulatory regions at the C-terminus of the pyrin protein, that act in a distinct manner to regulate positively or negatively inflammasome activation. Furthermore, our results indicate that different mutations in pyrin regulatory domains have different functional impacts on the pyrin inflammasome which could contribute to the diversity of pyrin-associated autoinflammatory diseases.

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Section: Discussionsupporting

confidence: 84%

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

et al. 2023

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“…As has been already documented, M694V and M680I mutations substantially affect pyrin function reflecting severe FMF phenotype, especially in homozygotic or double heterozygotic state [54,55]. However, the impact of other pyrin mutations located outside MEFV exon 10 and 2 on IBD phenotype cannot be excluded, as studies included in the present meta-analysis lack relevant data [56].…”

Section: Discussionmentioning

confidence: 79%

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

Papadopoulos

Antoniadou

Ritis

et al. 2022

JGLD

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Background and Aims: Several studies have suggested that mutations in MEFV, the gene responsible for familial Mediterranean fever (FMF), are frequently detected in inflammatory bowel disease (IBD) patients. We aimed to provide further evidence regarding a potential correlation between MEFV gene mutations and IBD by identifying all relevant studies and analyzing their results. Methods: EMBASE, PubMed/MEDLINE, and Google Scholar were used to identify all studies that published until January 2021 and reported MEFV mutation patterns in patients with ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC) with or without a control group. The Newcastle-Ottawa quality assessment scale was used to appraise the quality of the included studies. Results: Thirteen observational studies, including 937 patients and 977 controls, were analyzed. MEFV mutation rate in IBD patients was 0.238 (95%CI: 0.209-0.270; I 2 =95%); MEFV mutated alleles were more frequent in IBD patients when compared with controls (p=0.03 for UC, p=0.01 for CD and IC). Subgroup analysis indicated that MEFV mutations were increased in patients with IC when compared with UC and CD (I 2 =91%, p<0.001). Patients with extra-intestinal manifestations and pancolitis had 2.57 (95%CI 1.07-6.14; p=0.03) and 2.02 (95%CI: 1.01-4.04, P=0.049) odds ratios to carry MEFV mutant genotypes, respectively. Exon 10 mutations had the most serious impact. No source of heterogeneity was detected. Conclusions: MEFV mutations are common in IBD and are linked with the presence of extra-intestinal manifestations and pancolitis. Further research to assess the clinical significance and evolutionary significance of MEFV mutations in IBD patients is warranted.

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“…Heterozygous forms of FMF have recently been described and grouped as PAAND (Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis). Pyrin overexpression induces constitutive inflammasome activation, leading to IL-1β and IL-18 overproduction [ 27 , 28 , 29 ].…”

Section: Classification Of Saidsmentioning

confidence: 99%

What General Neurologists Should Know about Autoinflammatory Syndromes?

de Moraes,

do Nascimento,

Abrantes

et al. 2023

Brain Sciences

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Autoinflammatory disorders encompass a wide range of conditions with systemic and neurological symptoms, which can be acquired or inherited. These diseases are characterized by an abnormal response of the innate immune system, leading to an excessive inflammatory reaction. On the other hand, autoimmune diseases result from dysregulation of the adaptive immune response. Disease flares are characterized by systemic inflammation affecting the skin, muscles, joints, serosa, and eyes, accompanied by unexplained fever and elevated acute phase reactants. Autoinflammatory syndromes can present with various neurological manifestations, such as aseptic meningitis, meningoencephalitis, sensorineural hearing loss, and others. Early recognition of these manifestations by general neurologists can have a significant impact on the prognosis of patients. Timely and targeted therapy can prevent long-term disability by reducing chronic inflammation. This review provides an overview of recently reported neuroinflammatory phenotypes, with a specific focus on genetic factors, clinical manifestations, and treatment options. General neurologists should have a good understanding of these important diseases.

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The Changing Concepts Regarding the Mediterranean Fever Gene: Toward a Spectrum of Pyrin-Associated Autoinflammatory Diseases with Variable Heredity

Cited by 16 publications

References 39 publications

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

Mutations in the B30.2 and the central helical scaffold domains of pyrin differentially affect inflammasome activation

MEFV Mutations in IBD Patients: A Systematic Review and Meta- analysis

What General Neurologists Should Know about Autoinflammatory Syndromes?

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