Involvement of the Same TNFR1 Residue in Mendelian and Multifactorial Inflammatory Disorders

Abstract

Objectives TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92.Methods TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1.ResultsA TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p<5.10−4). It was associated with very high disease penetrance (0.9). Prediction of its impact on the protein structure revealed local conformational changes and alterations of the receptor electrostatic properties. R92W also impairs the TNFR1 expression at the cell surface and the levels of soluble receptor. Similar results were obtained with R92P, another mutation previously identified in a very small familial form with incomplete penetrance and variable expressivity. In contrast, TNFR1-R92Q behaves like the wild-type receptor.ConclusionsThese data demonstrate the pathogenicity of a mutation affecting arginine 92, a residue whose involvement in inflammatory disorders is deeply debated. Combined with previous reports on arginine 92 mutations, this study discloses an unusual situation in which different amino acid substitutions at the same position in the protein are associated with a clinical spectrum bridging Mendelian to multifactorial conditions.

Inspissated bile syndrome in an infant with citrin deficiency and congenital anomalies of the biliary tract and esophagus: Identification and pathogenicity analysis of a novel SLC25A13 mutation with incomplete penetrance

“…Non-penetrance refers to the lack of clinical signs and symptoms in genetically affected individuals. This phenomenon is not uncommon, not only in Mendelian disorders inherited as autosomal dominant traits ( 63 , 64 ), but also in some autosomal recessive diseases, such as Brown-Vialetto-Van Laere syndrome ( 65 ) and Wolfram syndrome ( 66 ). Whether or not CD penetrance is complete has remained an unresolved issue for years ( 27 ).…”

Anakinra and canakinumab for patients with R92Q-associated autoinflammatory syndrome: a multicenter observational study from the AIDA Network

“…Differently from what is demonstrated for structural mutations, neither accumulation of misfolded receptors in the cytoplasm, nor altered expression in cell membranes, nor defective shedding of the receptor–which are the mechanisms responsible of the increased production of IL-1 and the downstream pro-inflammatory cascade in TRAPS patients–have been observed. 17 , 18 , 35 , 36 According to this view, patients with an autoinflammatory phenotype due to the presence of R92Q may be expected to exhibit a different response rate to IL-1 blockade than that documented in patients with structural TRAPS-related mutations.…”

Clinical Overlapping in Autoinflammatory Diseases: The Role of Gene Duplication

“…An example should be the Crohn’s disease, one of the first investigated complex diseases in which NOD2 gene [responsible for Blau syndrome (BS)] was identified as a susceptibility gene. More recently, Jéru and colleagues describe the pathogenicity of a mutation affecting the same residue in TNFR1 in both Mendelian TRAPS syndrome and multifactorial inflammatory conditions (early arthritis, AA amyloidosis in juvenile idiopathic arthritis, multiple sclerosis, as examples) (4). …”