Mutations in NALP12 cause hereditary periodic fever syndromes

Abstract

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-B signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.genetics ͉ Mendelian disorder ͉ NLRP ͉ autoinflammatory disorder ͉ CATERPILLER

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis

“…11 Germline mutations in NLRP3 and NLRP12 are associated with hereditary periodic fever syndromes. 12,13 Although the function of NLRP9 and NLRP11 is not well understood, NLRP2 is suggested to function as a modulator of macrophage nuclear factor-kB activation and caspase-1 activation, 14 which may cause inflammation. All the evidences support that duplications of the NRLP gene cluster may significantly contribute to s-JIA pathogenesis in the patient.…”

Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes

“…To date, only a nonsense mutation and a splice site mutation have been identified in NLRP12, in familial forms of PFS (1). In the present study, we identified a missense mutation (p.Arg352Cys) within the NBS domain of the protein in 2 unrelated patients.…”

“…The wild-type NLRP12 expression vector (designated pNLRP12-WT) has been described previously (1). Site-directed mutagenesis was performed to generate the pNLRP12-Arg352Cys expression plasmid.…”

“…Recently, the first two recognized disease-causing mutations (a nonsense mutation and a splice site mutation) have been identified in the NLRP12 gene (also known as NALP12 or MONARCH-1) in patients with a clinical picture suggestive of a cryopyrin-associated periodic syndrome (CAPS) (1). CAPS represent a subgroup of PFS comprising the familial cold-induced autoinflammatory syndrome, the Muckle-Wells syndrome, and the chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease.…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…NLRP12 mutations are associated with hereditary periodic fever syndromes, and while NLRP12 shares strong homology with NLRP3, it is not involved in inflammasome formation but regulates the NF-kB cascade. 90,91 A nonsense mutation causing defective splicing and introducing a premature stop codon in NLRP12 causes a dominant phenotype due to the lack of regulation of the inflammatory pathway.…”