Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation.
medRxiv
; 2024 May 17.
Article
en En
| MEDLINE
| ID: mdl-38798321
ABSTRACT
IKKα, encoded by CHUK , is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKß. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in canonical NF-κB target gene expression in human.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
MedRxiv
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Estados Unidos