Abstract |
Immunodeficiency patients with DNA repair defects exhibit radiosensitivity and proneness to leukemia/ lymphoma formation. Though progress has been made in identifying the underlying mutations, in most patients the genetic basis is unknown. Two de novo mutated candidate genes, MCM3AP encoding germinal center-associated nuclear protein (GANP) and POMP encoding proteasome maturation protein (POMP), were identified by whole-exome sequencing (WES) and confirmed by Sanger sequencing in a child with complex phenotype displaying immunodeficiency, genomic instability, skin changes, and myelodysplasia. GANP was previously described to promote B-cell maturation by nuclear targeting of activation-induced cytidine deaminase (AID) and to control AID-dependent hyperrecombination. POMP is required for 20S proteasome assembly and, thus, for efficient NF-κB signaling. Patient-derived cells were characterized by impaired homologous recombination, moderate radio- and cross-linker sensitivity associated with accumulation of damage, impaired DNA damage-induced NF-κB signaling, and reduced nuclear AID levels. Complementation by wild-type (WT)-GANP normalized DNA repair and WT-POMP rescued defective NF-κB signaling. In conclusion, we identified for the first time mutations in MCM3AP and POMP in an immunodeficiency patient. These mutations lead to cooperative effects on DNA recombination and damage signaling. Digenic/polygenic mutations may constitute a novel genetic basis in immunodeficiency patients with DNA repair defects.
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Authors | Susanne A Gatz, Daniela Salles, Eva-Maria Jacobsen, Thilo Dörk, Tobias Rausch, Sevtap Aydin, Harald Surowy, Meta Volcic, Walther Vogel, Klaus-Michael Debatin, Adrian M Stütz, Klaus Schwarz, Ulrich Pannicke, Timo Hess, Jan O Korbel, Ansgar S Schulz, Johannes Schumacher, Lisa Wiesmüller |
Journal | Human mutation
(Hum Mutat)
Vol. 37
Issue 3
Pg. 257-68
(Mar 2016)
ISSN: 1098-1004 [Electronic] United States |
PMID | 26615982
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 WILEY PERIODICALS, INC. |
Chemical References |
- Intracellular Signaling Peptides and Proteins
- Molecular Chaperones
- proteasome maturation protein
- Acetyltransferases
- MCM3AP protein, human
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Topics |
- Acetyltransferases
(genetics)
- DNA Damage
(genetics, physiology)
- DNA Repair
(genetics, physiology)
- Humans
- Immunologic Deficiency Syndromes
(genetics)
- Intracellular Signaling Peptides and Proteins
(genetics)
- Molecular Chaperones
(genetics)
- Mutation
(genetics)
- Signal Transduction
(genetics, physiology)
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