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Ann Paediatr Rheum. 2012; 1(Supplement 1): 7-7

A Novel Mutation (Ser59Pro) in the TNFRSF1A Gene Associated with Adult- Onset Sporadic Traps

Alessandra Gava, Laura Obici, Laura Valzolgher, Simona Donadei, Paolo Sfriso, Eliana Greco, Paola Galozzi, Giampaolo Merlini, Leonardo Punzi.

Background: TRAPS is an autosomal dominant autoinflammatory disease, caused by mutations in the TNFRSF1A gene. To date 68 variants have been identified. Attacks are associated with fever, abdominal pain, myalgias and skin rash. Long term inflammatory response can lead to AA amyloidosis. Genetic testing confirms the diagnosis. We herein report an apparently sporadic case of TRAPS manifesting after the age of 40 years and associated with a novel mutation in exon 3 of the TNFRSF1A gene.

Methods: A 69 ys old man was evaluated for a chronic inflammatory characterized by fever, leukocytosis, refractory iron-deficiency anaemia, recurrent bronchopneumonias, palpebral ptosis, episodes of arthralgia, myalgia, cutaneous erythematosus lesions migrant and intermittent to limbs and trunk, and one episode of pericarditis. Serum IgD, IgA and SAA, along with the main acute phase protein response, were elevated. Since the clinical aspects were suggestive for an autoinflammatory syndrome, we decided to investigate mutations involved in TRAPS, MKD and cryopyrin-associated periodic syndromes (CAPS). Genomic DNA was isolated from peripheral blood lymphocytes by standard methods. Sequencing of MVK, TNFRSF1A and NLRP3 genes was performed by means of an automatic sequencer. Congo Red Dye Test was made for amyloid deposits research. The technique involves sterilizing and anesthetizing a small area of the anterior abdominal wall. Subcutaneous fat is then aspirated into a syringe. The small bits of fat obtained are crushed under a glass slide and stained with Congo red. Positive staining with the Congo red stain is indicated by apple-green birefringence utilizing a polarized microscope.

Results: Genetic testing was negative for MVK and NLRP3 mutations. Sequencing of the TNFRSF1A gene showed the presence of an heterozygous single-base mutation (c.262T>C) in exon 3, resulting in a Pro for Ser amino acid substitution at residue 59 of the mature protein (S59P), which has not been reported before in any TRAPS patient. Moreover, this mutation was not identified in 200 control chromosomes. Subcutaneous fat aspirate was negative for amyloid deposits.

Conclusion: The new S59P variant is located in a region of the receptor that is crucial for its function and is predicted to result in a protein conformational change: we are developing functional tests in order to assess this aspect. Overall, this mutation is likely to be responsible for our patient’s disease. More studies should be made in order to investigate also the concentration of the soluble receptor of TNF. At present, the disease is controlled with steroids.

Key words: A Novel Mutation (Ser59Pro) in the TNFRSF1A Gene Associated with Adult- Onset Sporadic Traps

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