Genetics and pathophysiology of the hereditary periodic fever syndromes.
| Disease . | Chromosome . | Gene . | Protein . | Proposed Pathophysiology . |
|---|---|---|---|---|
| Familial Mediterranean fever (FMF) | 16p13.3 | MEFV | Pyrin (also known as marenostrin) | Disorder in the regulation of interleukin (IL)-1β activation; possible abnormalities in nuclear factor (NF-κB) activation, leukocyte apoptosis, as well |
| TNF receptor–associated periodic syndrome (TRAPS) | 12p13 | TNFRSF1A | TNFRSF1A (TNFR1, p55, CD120a) | Impaired ectodomain cleavage of p55 receptor with stimulation; impaired trafficking of mutant receptors possibly causing constitutive NF-κB activation; impaired ligand-binding (resulting in preferential stimulation through p75?); impaired tumor necrosis factor (TNF)-stimulated leukocyte apoptosis |
| Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) | 12q24 | MVK | Mevalonate kinase (MK) | Accumulation of mevalonic acid, the substrate of the MK enzyme or deficiency in isoprenoids (products of the mevalonate pathway). Phenotype unlikely to be due to excessive IgD or cholesterol deficiency (another product of the mevalonate pathway). |
| The cryopyrinopathies (familial cold urticaria, Muckle-Wells, neonatal-onset multisystem inflammatory disease) | 1q44 | CIAS1 (also known as NALP3, PYPAF1, CATERPILLER 1.1) | Cryopyrin (or NALP3, PYPAF1, CATERPILLER 1.1) | Activating mutations in the cryopyrin/NALP3 protein, leading to increased activity of the inflammasome, and consequently excessive production of interleukin (IL)-1β; mutant cryopyrin shows increased sensitivity to activation by muramyl dipeptide. |
| Disease . | Chromosome . | Gene . | Protein . | Proposed Pathophysiology . |
|---|---|---|---|---|
| Familial Mediterranean fever (FMF) | 16p13.3 | MEFV | Pyrin (also known as marenostrin) | Disorder in the regulation of interleukin (IL)-1β activation; possible abnormalities in nuclear factor (NF-κB) activation, leukocyte apoptosis, as well |
| TNF receptor–associated periodic syndrome (TRAPS) | 12p13 | TNFRSF1A | TNFRSF1A (TNFR1, p55, CD120a) | Impaired ectodomain cleavage of p55 receptor with stimulation; impaired trafficking of mutant receptors possibly causing constitutive NF-κB activation; impaired ligand-binding (resulting in preferential stimulation through p75?); impaired tumor necrosis factor (TNF)-stimulated leukocyte apoptosis |
| Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) | 12q24 | MVK | Mevalonate kinase (MK) | Accumulation of mevalonic acid, the substrate of the MK enzyme or deficiency in isoprenoids (products of the mevalonate pathway). Phenotype unlikely to be due to excessive IgD or cholesterol deficiency (another product of the mevalonate pathway). |
| The cryopyrinopathies (familial cold urticaria, Muckle-Wells, neonatal-onset multisystem inflammatory disease) | 1q44 | CIAS1 (also known as NALP3, PYPAF1, CATERPILLER 1.1) | Cryopyrin (or NALP3, PYPAF1, CATERPILLER 1.1) | Activating mutations in the cryopyrin/NALP3 protein, leading to increased activity of the inflammasome, and consequently excessive production of interleukin (IL)-1β; mutant cryopyrin shows increased sensitivity to activation by muramyl dipeptide. |