Heterogeneity among patients with tumor necrosis factor receptor–associated periodic syndrome phenotypes

Aganna, Ebun; Hammond, L. J.; Hawkins, Philip N.; Aldea, Anna; McKee, Shane; Amstel, Hans Kristian Ploos van; Mischung, Claudia; Kusuhara, Koichi; Saulsbury, Frank T.; Lachmann, HJ; Bybee, A; McDermott, Elizabeth; Regina, Micaela La; Aróstegui, Juan I.; Campistol, Josep M.; Worthington, Sharron; High, Kevin P.; Molloy, Michael G.; Baker, Nicholas; Bidwell, Jeff L.; Castañer, J.; Whiteford, Margo; Janssens-Korpola, P. L.; Manna, Raffaele; Powell, Richard J.; Woo, Patricia; P, Solís; Minden, Kirsten; Frenkel, Joost; Yagüe, Jordi; Mirakian, Rita; Hitman, G. A.; McDermott, Michael

doi:10.1002/art.11215

Cited by 182 publications

(141 citation statements)

References 35 publications

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“…2,4 However, the defective shedding is neither correlated with the presence of TNFRSF1A gene mutations nor necessary for the development of TRAPS. Indeed, an impaired TNFRSF1A shedding was not present in TRAPS patients with C30S, T37I, R42Q, del42, C52R and N65I TNFRSF1A mutations, 2,5,6 but it was observed in affected members of three TNFRSF1A mutation-negative families. 6 Supplementary investigations must be performed to understand the exact molecular mechanisms of TRAPS and the significance of an impaired TNFRSF1A shedding.…”

Section: Discussionmentioning

confidence: 89%

Unexpected high frequency of P46L TNFRSF1A allele in sub-Saharan West African populations

et al. 2004

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TNF receptor-associated periodic syndrome (TRAPS) is an autosomal dominant disorder characterized by recurrent attacks of fever and serositis. To date, more than 30 mutations have been reported in TNFRSF1A, the responsible gene. In Caucasian populations, the P46L (c.224C4T) TNFRSF1A sequence variation is considered as a low-penetrance mutation because its allele frequency is similar in patients and controls (B1%). Whereas the spectrum of TNFRSF1A gene mutations has been well established in Caucasian and several Mediterranean populations, it remains unknown in sub-Saharan African populations. In this study, we found an unexpected high P46L allele frequency (B10%) in two groups from West Africa -a group of 145 patients with sickle cell anaemia and a group of 349 healthy controls. These data suggest that the P46L variant is rather a polymorphism than a TRAPS causative mutation. We propose that the P46L high frequency in West African populations could be explained by some biological advantage conferred to carriers.

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Section: Discussionmentioning

confidence: 89%

Unexpected high frequency of P46L TNFRSF1A allele in sub-Saharan West African populations

et al. 2004

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“…Impaired cleavage of the TNFRI (p55) ectodomain upon cellular activation has been demonstrated as a pathogenic mechanism in some but not all TNFRI variants (3-6) and did not relate to the severity of the phenotype (7,8).…”

Section: Objective To Investigate the Molecular Consequences Of Exprmentioning

confidence: 99%

“…2), mostly located in either the first or second cysteine-rich N-terminal extracellular domain (CRD1 or CRD2) of TNFRSF1A (2,3). Impaired cleavage of the TNFRI (p55) ectodomain upon cellular activation has been demonstrated as a pathogenic mechanism in some but not all TNFRI variants (3-6) and did not relate to the severity of the phenotype (7,8).…”

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confidence: 99%

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Yousaf¹,

Gould²,

Aganna³

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the molecular consequences of expressing mutated forms of tumor necrosis factor receptor I (TNFRI) as found in patients with TNFR-associated periodic syndrome (TRAPS).Methods. We cloned and expressed full-length wild-type (WT) and T50K and P46L variants of TNFRI using a new tightly regulated doxycycline-dependent expression system. This system enabled the study of molecular interactions between these receptors at both physiologic and pathophysiologic levels of expression.Results. We used chemical crosslinking on the cell surface to show that WT and mutant forms of TNFRI, derived from TRAPS patients, interact in the absence of TNF ligand. Doxycycline-controlled up-regulation of one TNFRI allele, either WT or mutant, caused downregulation of the other allele, indicating dynamic control of cell surface assembly. We also demonstrated that increased expression of mutant TNFRI (T50K) was associated with a parallel increase in NF-B p65 (RelA) subunit activation, which did not occur with increased expression of WT TNFRI.Conclusion. The T50K TRAPS-related variant is capable of sustaining inappropriate NF-B activation, resulting in persistent autoinflammation in target organs such as skin, synovial membrane, and the central nervous system. We conclude that some of the inflammatory processes seen in TRAPS do not involve direct interaction of TNF with its receptors, but that other proinflammatory mechanisms capable of up-regulating TNFRI expression may cause cellular activation through the NF-B signaling pathway.Tumor necrosis factor receptor-associated periodic syndrome (TRAPS; MIM no. 142680) is a dominantly inherited chronic inflammatory disorder caused by mutations in the extracellular domains of tumor necrosis factor receptor I (TNFRI), the gene for which is TNFRSF1A (1), and characterized by recurrent fevers and abdominal pain. The most common mutations involve cysteine residues, but several variants involving other residues have also been reported (1,2). More than 30 different pathogenic TNFRSF1A mutations have now been identified (see http://fmf.igh.cnrs.fr/infevers/ and ref.2), mostly located in either the first or second cysteine-rich N-terminal extracellular domain (CRD1 or CRD2) of TNFRSF1A (2,3). Impaired cleavage of the TNFRI (p55) ectodomain upon cellular activation has been demonstrated as a pathogenic mechanism in some but not all TNFRI variants (3-6) and did not relate to the severity of the phenotype (7,8).Biologic activities of TNF are mediated through 2 TNFRs, TNFRI and TNFRII (TNFR superfamily 1B

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“…Indeed, many conflicting data on the function of HPF proteins and associated mutations have been generated by different teams even when using similar experimental systems (e.g., 11,12). In addition, HPFs remain genetically unexplained in a very large number of patients (13)(14)(15)(16), raising the question of whether one or several other genes are responsible for these periodic fever syndromes. Although positional cloning has been of great help to identify HPF genes, 6 years have passed since the last gene was shown to be involved in these disorders.…”

mentioning

confidence: 99%

Mutations in NALP12 cause hereditary periodic fever syndromes

Jéru

Duquesnoy

Fernandes-Alnemri

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

342

235

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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

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Heterogeneity among patients with tumor necrosis factor receptor–associated periodic syndrome phenotypes

Cited by 182 publications

References 35 publications

Unexpected high frequency of P46L TNFRSF1A allele in sub-Saharan West African populations

Unexpected high frequency of P46L TNFRSF1A allele in sub-Saharan West African populations

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

Mutations in NALP12 cause hereditary periodic fever syndromes

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