RESUMO
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis (peritonitis, pleuritis, or synovitis), and erysipelas-like erythema. Genetic variants in the MEFV gene are associated with this disease. Familial Mediterranean fever is considered an autosomal recessive disease. However, in Middle Eastern countries, a third of the patients expressing FMF manifestations, carry a single mutation only. Moreover, some cases of pure dominant inheritance linked to specific single MEFV variants have also been described. This complex inheritance of MEFV-associated inflammatory diseases poses a serious challenge when interpreting the results of genetic testing in patients having recurrent fever syndromes. In addition, in certain situations, asymptomatic individuals may be incidentally found to carry MEFV variants. These cases pose the question of their exact diagnosis and whether they should be treated. Previous studies have focused on genetic results interpretations among symptomatic patients. In the current article, we would like to elaborate on the genetic interpretation in cases of symptomatic individuals suspected to have FMF and on asymptomatic individuals carrying MEFV variants. We aim to assist physicians unfamiliar with FMF to cope with genetic results interpretation when facing symptomatic and asymptomatic individuals carrying MEFV variants and suggest a management plan accordingly.
Assuntos
Febre Familiar do Mediterrâneo , Mutação , Pirina , Humanos , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/diagnóstico , Pirina/genética , Predisposição Genética para Doença , Testes Genéticos , Variação GenéticaRESUMO
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.
Assuntos
Mutação com Ganho de Função , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Mutação com Ganho de Função/genética , Inflamassomos/genética , Desenvolvimento de Medicamentos , SíndromeRESUMO
AUTOINFLAMMATORY DISEASES IN CHILDREN: THE CONTRIBUTION OF GENETICS. Autoinflammatory diseases (AIDs) have benefited from modern genetic tools, in particular the widespread use of high-throughput sequencing, which has helped to improve our knowledge of the inheritance patterns of AIDs, whether hereditary or multifactorial. The case for genetic testing has become compelling. However, the new modes of inheritance revealed in recent years complicate genetic counselling and justify close collaboration between clinicians and biologists during multidisciplinary clinical meetings.
MALADIES AUTO-INFLAMMATOIRES DE L'ENFANT : APPORT DE LA GÉNÉTIQUE. Les maladies auto-inflammatoires (MAI) ont bénéficié des outils modernes de la génétique, notamment de la généralisation du séquençage en haut débit ayant participé à l'amélioration des connaissances concernant les modes de transmission des MAI, héréditaires ou multifactorielles. Les arguments en faveur d'une indication de test génétique sont devenus incontournables pour les MAI. Or les nouveaux modes de transmission héréditaires révélés ces dernières années rendent compliqué le conseil génétique et justifient l'étroite collaboration entre cliniciens et biologistes lors de réunions cliniques pluridisciplinaires.