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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.

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  • Authors+Show Affiliations

    ,

    Section of Genetics, Arthritis and Rheumatism Branch, National Institutes of Health, Bethesda, MD 20892, USA. aksentii@exchange.nih.gov

    , , , , , , , , , , , ,

    Source

    American journal of human genetics 69:2 2001 Aug pg 301-14

    MeSH

    Alternative Splicing
    Amino Acid Sequence
    Amyloidosis
    Antigens, CD
    Base Sequence
    DNA Mutational Analysis
    Ethnic Groups
    Exons
    Familial Mediterranean Fever
    Female
    Genetic Heterogeneity
    Haplotypes
    Humans
    Introns
    Male
    Microsatellite Repeats
    Models, Molecular
    Molecular Sequence Data
    Mutation
    Pedigree
    Penetrance
    Polymorphism, Single Nucleotide
    Protein Structure, Tertiary
    Receptors, Tumor Necrosis Factor
    Receptors, Tumor Necrosis Factor, Type I

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    11443543

    Citation

    Aksentijevich, I, et al. "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." American Journal of Human Genetics, vol. 69, no. 2, 2001, pp. 301-14.
    Aksentijevich I, Galon J, Soares M, et al. 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. Am J Hum Genet. 2001;69(2):301-14.
    Aksentijevich, I., Galon, J., Soares, M., Mansfield, E., Hull, K., Oh, H. H., ... Kastner, D. L. (2001). 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. American Journal of Human Genetics, 69(2), pp. 301-14.
    Aksentijevich I, et al. 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. Am J Hum Genet. 2001;69(2):301-14. PubMed PMID: 11443543.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Aksentijevich,I, AU - Galon,J, AU - Soares,M, AU - Mansfield,E, AU - Hull,K, AU - Oh,H H, AU - Goldbach-Mansky,R, AU - Dean,J, AU - Athreya,B, AU - Reginato,A J, AU - Henrickson,M, AU - Pons-Estel,B, AU - O'Shea,J J, AU - Kastner,D L, Y1 - 2001/07/06/ PY - 2001/04/12/received PY - 2001/06/06/accepted PY - 2001/7/10/pubmed PY - 2001/8/17/medline PY - 2001/7/10/entrez SP - 301 EP - 14 JF - American journal of human genetics JO - Am. J. Hum. Genet. VL - 69 IS - 2 N2 - 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. SN - 0002-9297 UR - https://www.unboundmedicine.com/medline/citation/11443543/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61077-5 DB - PRIME DP - Unbound Medicine ER -