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P02-014 - Consequences of Arginine 92 mutations in TNFR1
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Edité par CCSD -
International audience. IntroductionTNFRSF1A is involved in a Mendelian autosomal dominant autoinflammatory disorder called TNFR-associatedperiodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affectingconserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequentR92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor tomultifactorial inflammatory disorders.ObjectivesThis study investigates TRAPS pathophysiology in a family exceptional by its size (13 members).MethodsTNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electro-static properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1expression was assessed by western blotting and ELISA in lysates and supernatants of HEK293T cells transfectedwith plasmids encoding wild-type and mutated TNFR1.ResultsA TNFRSF1A heterozygous missense mutation, R92W(c.361C>T) perfectly segregated with typical TRAPS mani-festations within the family (p<5.10-4), and was associated with very high disease penetrance (0.9). Prediction of its impact on protein structure revealed local conformational changes and alterations of electrostatic properties. In addition, R92W leads to abrogation of the receptor shedding, whereas TNFR1-R92Q behaves like the wild-type receptor.ConclusionThese data demonstrate the pathogenicity of a mutation affecting arginine 92, a residue whose involvement ininflammatory disorders is deeply debated. Combined with previous data on arginine 92 mutations, this studydiscloses an unusual situation in which different amino acid substitutions at the same position in the protein areassociated with a clinical spectrum bridging Mendelian to multifactorial conditions.
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