Late-onset expression of an autoinflammatory disease: Identification and functional characterization of a mosaic variant in NLRC4 - Inserm - Institut national de la santé et de la recherche médicale
Poster De Conférence Année : 2024

Late-onset expression of an autoinflammatory disease: Identification and functional characterization of a mosaic variant in NLRC4

Farah Diab
Rahma Mani
Florence Dastot Le Moal
William Piterboth

Résumé

Background/Objectives: NLRC4 gene encodes an essential component of the NLRC4 inflammasome, a multiprotein complex involved in activating inflammatory pathways. Germline NLRC4 variations are associated with severe forms of autoinflammatory diseases (AID) in children, often involving enterocolitis and potentially leading to macrophage activation syndrome. Somatic mosaic variations in NLRC4 have been reported in only two adult patients. This study aimed to identify the molecular basis of adult-onset AID without macrophage activation syndrome. Methods: The study involved deep sequencing of the patient's leukocyte genomic DNA through a panel of AID genes and functional evaluation of the identified NLRC4 variation in HEK293T cells expressing different protein partners (ASC and Caspase1) enabling the detection of specks, a hallmark of NLRC4 inflammasome activation. NF-κB pathway activation was also studied by a reporter gene system. Results: The patient, a 28-year-old man, had a history of unlabeled psychosis since the age of 19, and severe inflammatory episodes from the age of 21. Sequencing revealed the presence of a mosaic variation in NLRC4, c.398C>T p.(Thr133Ile), with the mutant allele represented at a ratio of 5%. Functional studies demonstrated that this variation has a gainof- function pathogenic effect on inflammation, as evidenced by a significant increase in the percentage of specks in cells expressing mutant NLRC4 and the activation of the NF-κB pathway. Conclusion: This study identified a novel mosaic variation of NLRC4 associated with adultonset autoinflammatory disease (AID) without macrophage activation syndrome, and demonstrated its gain-of-function pathogenic effect on inflammation.
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Dates et versions

inserm-04674678 , version 1 (21-08-2024)

Identifiants

  • HAL Id : inserm-04674678 , version 1

Citer

Farah Diab, Camille Louvrier, Marc Fabre, Mira Rabbaa, Aphrodite Daskalopoulou, et al.. Late-onset expression of an autoinflammatory disease: Identification and functional characterization of a mosaic variant in NLRC4. European Society of Human Genetics, Jun 2024, Berlin (Germany), Germany. ⟨inserm-04674678⟩
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