Late-onset expression of an autoinflammatory disease: Identification and functional characterization of a mosaic variant in NLRC4
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.
Mots clés
CARD
caspase recruitment domain CRP
C-reactive protein EV
Empty Vector Hb
hemoglobin NAIP
nucleotide-binding leucine-rich repeat family apoptosis inhibitory protein NLRC4
nucleotide-binding leucine-rich repeat family NLRC4 Activated NAIP Inflammasome
caspase recruitment domain
CRP
C-reactive protein
Empty Vector
hemoglobin
NAIP
nucleotide-binding leucine-rich repeat family apoptosis inhibitory protein
NLRC4
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