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
| Autor: | Miguel Luz Soares, Jérôme Galon, Michael Henrickson, Antonio J. Reginato, Hye-Hyun Oh, Raphaela Goldbach-Mansky, Daniel L. Kastner, Bernardo A. Pons-Estel, Jane Dean, Balu Athreya, John J. O'Shea, Ivona Aksentijevich, Keith M. Hull, Elizabeth Mansfield |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Models Molecular DNA Mutational Analysis Molecular Sequence Data Penetrance Biology Polymorphism Single Nucleotide Receptors Tumor Necrosis Factor Exon Genetic Heterogeneity Antigens CD Genotype medicine Ethnicity Genetics Humans Genetics(clinical) Amino Acid Sequence Genetics (clinical) Base Sequence Genetic heterogeneity Amyloidosis Haplotype Exons Articles medicine.disease Phenotype Introns Familial Mediterranean Fever Pedigree Protein Structure Tertiary Alternative Splicing Haplotypes TNF receptor associated periodic syndrome Receptors Tumor Necrosis Factor Type I Mutation Female Microsatellite Repeats |
| Zdroj: | The American Journal of Human Genetics. 69(2):301-314 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/321976 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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