Loss-of-function mutation in ZNF74 is associated with a novel primary immunodeficiency and T cell intrinsic BHLHE40 de-repression

Meyer, Benedikt Jonas. Loss-of-function mutation in ZNF74 is associated with a novel primary immunodeficiency and T cell intrinsic BHLHE40 de-repression. 2021, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/85492/

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KRAB zinc finger proteins (KZFP) are a large family of epigenetic repressors with pleiotropic functions. While the KZFP co-factor KAP-1 has been extensively studied, the physiologic function of individual KZFP members is largely unknown. Within a cohort of patients with primary immunodeficiency (PID), we identified two brothers carrying a homozygosity region on chromosome 22q11 with a truncating loss-of-function mutation in ZNF74 combined with a known disease-associated variant in ADA2. As deficiency of ADA2 (DADA2) has a very variable clinical phenotype, incomplete penetrance and is likely influenced by mutations in modifying genes, we tested the possible influence of the truncating loss-of-function mutation in ZNF74 on the observed clinical phenotype. Analyzing published ChIP-exo-seq data of ZNF74 revealed a binding peak close to an enhancer cluster of BHLHE40, a transcription factor which was highly up-regulated in CD4+ T cell subsets from the index patient. Wild type but not mutant ZNF74 bound to the specific BHLHE40 enhancer site and repressed BHLHE40 in vitro underlining that the BHLHE40 up-regulation seen in the index patient is likely caused by the ZNF74 loss-of-function. Furthermore, transcriptomic analysis of CD4+ T cell subsets from the index patient revealed a tissue resident memory (Trm)-like signature of circulating T cells likely activated by the BHLHE40 de-repression. This could be clinically linked to excessive lymphoma-like T cell infiltrations in skin and bone marrow and an altered memory T cell compartment. Thus, we report the first homozygous loss-of-function mutation in a human KZFP contributing to immune-dysregulation.
Advisors:Hess, Christoph and Recher, Mike and Manz, Markus G
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C)
UniBasel Contributors:Hess, Christoph and Recher, Mike
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14564
Thesis status:Complete
Number of Pages:99
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss145643
edoc DOI:
Last Modified:01 Dec 2023 02:30
Deposited On:12 Jan 2022 08:31

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