The Tumor-Necrosis-Factor Receptor–Associated Periodic Syndrome: New Mutations in TNFRSF1A, Ancestral Origins, Genotype-Phenotype Studies, and Evidence for Further Genetic Heterogeneity of Periodic Fevers

• Published in: American journal of human genetics Vol. 69; no. 2; pp. 301 - 314
• Main Authors: Aksentijevich, Ivona, Galon, Jérôme, Soares, Miguel, Mansfield, Elizabeth, Hull, Keith, Oh, Hye-Hyun, Goldbach-Mansky, Raphaela, Dean, Jane, Athreya, Balu, Reginato, Antonio J., Henrickson, Michael, Pons-Estel, Bernardo, O’Shea, John J., Kastner, Daniel L.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.08.2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Alternative Splicing - genetics; Amino Acid Sequence; Amyloidosis - genetics; Antigens, CD - chemistry; Antigens, CD - genetics; Base Sequence; Biological and medical sciences; DNA Mutational Analysis; Ethnic Groups - genetics; Exons - genetics; Familial Mediterranean Fever - genetics; Female; Genetic Heterogeneity; Haplotypes - genetics; Humans; Introns - genetics; Male; Medical sciences; Microsatellite Repeats - genetics; Models, Molecular; Molecular Sequence Data; Mutation - genetics; Pedigree; Penetrance; periodic-fever syndrome; Polymorphism, Single Nucleotide - genetics; Protein Structure, Tertiary; Receptors, Tumor Necrosis Factor - chemistry; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor, Type I; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; TNFRSF1A gene; tumor necrosis factor receptor-associated periodic syndrome; Human; Family study; Pathogenesis; Periodical; Cytokine; Genotype; Genetic determinism; Fever; Genetic disease; Heterogeneity; Phenotype; Gene; Tumor necrosis factor; Autosomal character; Dominant character; Mutation; Biological receptor
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/321976

Mutations in the extracellular domain of the 55-kD tumor-necrosis factor (TNF) receptor (TNFRSF1A), a key regulator of inflammation, define a periodic-fever syndrome, TRAPS ( TNF receptor– associated periodic syndrome [MIM 142680]), which is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and/or conjunctivitis; some patients also develop systemic amyloidosis. Elsewhere we have described six disease-associated TNFRSF1A mutations, five of which disrupt extracellular cysteines involved in disulfide bonds; four other mutations have subsequently been reported. Among 150 additional patients with unexplained periodic fevers, we have identified four novel TNFRSF1A mutations (H22Y, C33G, S86P, and c.193−14 G→A), one mutation (C30S) described by another group, and two substitutions (P46L and R92Q) present in ∼1% of control chromosomes. The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, argue that these are low-penetrance mutations rather than benign polymorphisms. The c.193−14 G→A mutation creates a splice-acceptor site upstream of exon 3, resulting in a transcript encoding four additional extracellular amino acids. T50M and c.193−14 G→A occur at CpG hotspots, and haplotype analysis is consistent with recurrent mutations at these sites. In contrast, although R92Q also arises at a CpG motif, we identified a common founder chromosome in unrelated individuals with this substitution. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TRAPS and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations. In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes.