Pathogenesis

Chae, Jae Jin; Kastner, Daniel L.

doi:10.1007/978-3-319-14615-7_2

Cited by 2 publications

(2 citation statements)

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“…At a mechanistic level, the recognition of pyrin, the protein encoded by MEFV, has also been consequential (25). Its presence in innate immune cells such as neutrophils, monocytes, dendritic cells, and serosal and synovial fibroblasts suggested a major role in the regulation of inflammation.…”

Section: New Concepts In Familial Mediterranean Fevermentioning

confidence: 99%

“…Nevertheless, a major mystery remained unsolved until recently: Does the pyrin protein serve as a sensor for some sort of microbial infection? That this might be the case was suggested both by the extraordinarily high carrier frequencies for MEFV that have been directly documented in certain populations, indicating the possibility of a selective advantage for the carriers (25), and by the fact that other innate immune molecules mutated in autoinflammatory disease, such as the above-mentioned NLRC4 and NLRP3, serve precisely such a function as pathogen sensors. Because there are strong data that IL-1β plays a central role in FMF, one can put the question in a somewhat different way: Is there a pyrin inflammasome, and if so, what triggers its activation?…”

Section: New Concepts In Familial Mediterranean Fevermentioning

confidence: 99%

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Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed

Stoffels

Kastner

2016

Annu. Rev. Genom. Hum. Genet.

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Autoinflammatory diseases are inborn disorders of the innate immune system characterized by episodes of systemic inflammation that are mediated largely by myeloid cells. The field of autoinflammatory diseases has been established since 1999, following the identification of the first genes underlying periodic fever syndromes. This review focuses on developments that have transformed the field in the last two years. We discuss three newly described monogenic autoinflammatory diseases [deficiency of adenosine deaminase 2 (DADA2), a subtype of macrophage activation syndrome (MAS), and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI)], discuss the possibilities of somatic mosaicism and digenic inheritance, and give an update on new concepts in pathways involved in familial Mediterranean fever (FMF). Finally, the new monogenic autoinflammatory disease haploinsufficiency of A20 (HA20) underscores the placement of monogenic diseases in the firmament of common autoinflammatory phenotypes. The advances in the last two years have shed light on the pathophysiology of several autoinflammatory diseases and have elucidated new pathways that play a role in innate immunity.

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Section: New Concepts In Familial Mediterranean Fevermentioning

confidence: 99%

Section: New Concepts In Familial Mediterranean Fevermentioning

confidence: 99%

Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed

Stoffels

Kastner

2016

Annu. Rev. Genom. Hum. Genet.

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Detection of a rare variant inPSTPIP1through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype

et al. 2023

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Objective The presence of familial Mediterranean fever (FMF) cases without MEFV pathogenic variants led us to search for other genes’ involvement in the disease development. Here, we describe the presence of genetic heterogeneity in a three-generation family with an FMF/mevalonate kinase deficiency(MKD)-overlapping phenotype without MEFV/MVK pathogenic variants. Method Targeted sequencing revealed a rare, fully penetrant variant in PSTPIP1 (p.Arg228Cys, rs781341816). Computational stability analyses of PSTPIP1 protein were performed. PSTPIP1-pyrin protein interaction was examined by immunoprecipitation and immunoblotting in peripheral blood mononuclear cells (PBMCs) of patients and healthy controls. PBMCs were cultured, and inflammation was induced by LPS+ATP treatment, followed by protein level measurements of caspase-1, IL1ß, pyrin, and PSTPIP1 in cell lysates and mature caspase-1 and mature IL1ß in supernatants. Results The conserved, rare (GnomAD, 0.000028) PSTPIP1 p.Arg228Cys variant, previously reported in ClinVar as a variant with uncertain significance, showed complete penetrance in the family presenting an autosomal dominant pattern. Computational analyses showed a potentially destabilizing effect of the variant on PSTPIP1 protein. Accordingly, PSTPIP1-pyrin interaction was increased in patients harboring the variant, which resulted in elevated levels of mature caspase-1 and IL1ß in the inflammation-induced patient samples. Conclusions Unlike previously described cases with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA)-associated PSTPIP1 variants, our patients with the p.Arg228Cys variant presented with an FMF/MKD-overlapping phenotype. As additional data on the genetic heterogeneity in the variable clinical spectrum of autoinflammatory syndromes, we suggest that the p.Arg228Cys variant in PSTPIP1 is related to inflammation responses through strong PSTPIP1-pyrin interaction and pyrin inflammasome activation.

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Pathogenesis

Cited by 2 publications

References 78 publications

Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed

Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed

Detection of a rare variant inPSTPIP1through three generations in a family with an initial diagnosis of FMF/MKD-overlapping phenotype

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