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Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

ABSTRACT: Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

PROVIDER: PRJNA1111916 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29044127_1.fastq.gz	Fastqsanger.gz
	SRR29044127_2.fastq.gz	Fastqsanger.gz
	SRR29044128_1.fastq.gz	Fastqsanger.gz
	SRR29044128_2.fastq.gz	Fastqsanger.gz
	SRR29044133_1.fastq.gz	Fastqsanger.gz

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Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

Project description:IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. 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 kinase dead mutants. Non-canonical NF-κB activation was abolished 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 both NF-κB pathways.

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