title: 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.
abstract: 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 approximately 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.
authors.affiliation: Section of Genetics, Arthritis and Rheumatism Branch, National Institutes of Health, Bethesda, MD 20892, USA. aksentii@exchange.nih.gov
authors.forename: I
authors.initials: I
authors.lastname: Aksentijevich
authors.forename: J
authors.initials: J
authors.lastname: Galon
authors.forename: M
authors.initials: M
authors.lastname: Soares
authors.forename: E
authors.initials: E
authors.lastname: Mansfield
authors.forename: K
authors.initials: K
authors.lastname: Hull
authors.forename: H H
authors.initials: HH
authors.lastname: Oh
authors.forename: R
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: J
authors.initials: J
authors.lastname: Dean
authors.forename: B
authors.initials: B
authors.lastname: Athreya
authors.forename: A J
authors.initials: AJ
authors.lastname: Reginato
authors.forename: M
authors.initials: M
authors.lastname: Henrickson
authors.forename: B
authors.initials: B
authors.lastname: Pons-Estel
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Shea
authors.forename: D L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000235:genetics; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005006:Ethnicity / Q000235:genetics; D005091:Exons / Q000235:genetics; D010505:Familial Mediterranean Fever / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I
chemical_list: D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I