NLRP3-associated autoinflammatory diseases: phenotypic and molecular characteristics of germline versus somatic mutations
Date
2020-04-02
Authors
Louvrier, Camille
Assrawi, Eman
El Khouri, Elma
Melki, Isabelle
Copin, Bruno
Bourrat, Emmanuelle
Lachaume, Noemie
Cador-Rousseau, Berengere
Duquesnoy, Philippe
Piterboth, William
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Background: NLRP3-associated autoinflammatory diseases
(NLRP3-AIDs) include conditions of various severities, due to
germline or somatic mosaic NLRP3 mutations.
Objective: To identify mosaic- versus germline-specific NLRP3
mutations’ characteristics, we reinterpreted all the mutations
reported in NLRP3-AIDs and performed an in-depth study of 3
novel patients.
Methods: The pathogenicity of all reported mosaic/germline
mutations was reassessed according to international
recommendations and their location on the NLRP3 3-
dimensional structure. Deep-targeted sequencing and NLRP3-
inflammasome-activation assays were used to identify the
disease-causing mutation in 3 patients.
Results: We identified, in 3 patients, mosaic mutations affecting
the same NLRP3 amino acid (Glu569). This residue belongs to 1
of the 2 mosaic mutational hot spots that face each other in the
core of the NLRP3 ATPase domain. The review of the 90 NLRP3
mutations identified in 277 patients revealed that those hot spots
account for 68.5% of patients (37 of 54) with mosaic mutations.
Glu569 is affected in 22% of the patients (12 of 54) with mosaic
mutations and in 0.4% of patients (1 of 223) with germline
mutations. Only 8 of 90 mutations were found in mosaic and
germinal states. All of the germline mutations were associated
with a severe phenotype. These data suggest that mutations
found only in mosaic state could be incompatible with life if
present in germinal state. None of the 5 most frequent germline
mutations was identified in mosaic state. Mutations found only
in germinal state could, therefore, be asymptomatic in mosaic
state.
Conclusions: The phenotypic spectrum of NLRP3-AIDs appears
to be related to the germinal/mosaic status and localization of
the underlying mutations. (J Allergy Clin Immunol
2020;145:1254-61.)
Description
Keywords
NLRP3-associated autoinflammatory diseases , NLRP3 , somatic mosaic mutations , NLRP3-inflammasome activation , mutational hot spot