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The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations
Keith M Hull1, Nitza Shoham, Jae Jin Chae
1Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. hullk@mail.nih.gov
Abstract:
The authors review the genes, and their respective proteins, responsible for eight autoinflammatory conditions. Familial Mediterranean fever is caused by mutations in pyrin, which is the prototype of a new family of proteins belonging to the death-domain superfamily. This new group of proteins, which regulate apoptosis, inflammation, and cytokine processing, share an approximately 90-amino-acid N-terminal sequence called the PYRIN domain. Mutations in another PYRIN domain protein, termed cryopyrin, are responsible for three clinically defined illnesses, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and NOMID/CINCA. A related protein encoded by the gene is responsible for the Mendelian disorder, Blau syndrome, and also predisposes to Crohn disease. The gene responsible for PAPA syndrome has recently been identified as, and preliminary results from the authors' laboratory also implicate its protein product in these pathways. Lastly, the authors discuss the broadening genetic and clinical spectrum of TRAPS, an autoinflammatory syndrome resulting from mutations in the 55-kDa receptor for tumor necrosis factor.
Insights
Genetic mutations in pyrin and cryopyrin proteins cause autoinflammatory conditions like Familial Mediterranean Fever and Muckle-Wells syndrome. Understanding these genetic links aids in diagnosing and treating these rare inflammatory diseases.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- Autoinflammatory conditions are a group of rare genetic disorders characterized by recurrent episodes of inflammation.
- These conditions arise from dysregulation of the innate immune system, often involving specific protein families.
Purpose of the Study:
- To review the genes and proteins implicated in eight distinct autoinflammatory conditions.
- To elucidate the role of PYRIN domain-containing proteins in the pathogenesis of these diseases.
Main Methods:
- Literature review of genetic and protein data related to autoinflammatory syndromes.
- Analysis of protein families, including the PYRIN domain superfamily and TNF receptor.
- Discussion of genetic mutations and their association with clinical phenotypes.
Main Results:
- Mutations in pyrin cause Familial Mediterranean Fever.
- Mutations in cryopyrin are linked to Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and NOMID/CINCA.
- Other PYRIN domain proteins and the TNF receptor are implicated in Blau syndrome, Crohn disease, PAPA syndrome, and TRAPS.
Conclusions:
- The PYRIN domain protein family plays a crucial role in regulating inflammation and apoptosis.
- Genetic defects in specific proteins are the underlying cause of a spectrum of autoinflammatory diseases.
- Further research into these genetic pathways can improve diagnosis and therapeutic strategies for autoinflammatory conditions.