title: MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child.
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.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Gatz
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salles
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Jacobsen
authors.affiliation: Gynecology Research Unit, Hannover Medical School, Hannover, D-30625, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
authors.forename: Sevtap
authors.initials: S
authors.lastname: Aydin
authors.affiliation: Department of Human Genetics, Ulm University, Ulm, D-89081, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Surowy
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
authors.forename: Meta
authors.initials: M
authors.lastname: Volcic
authors.affiliation: Department of Human Genetics, Ulm University, Ulm, D-89081, Germany.
authors.forename: Walther
authors.initials: W
authors.lastname: Vogel
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.affiliation: Institute of Transfusion Medicine, Ulm University and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg - Hessen, Ulm, D-89081, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Institute of Transfusion Medicine, Ulm University and Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg - Hessen, Ulm, D-89081, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.affiliation: Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, D-53127, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Hess
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
authors.forename: Ansgar S
authors.initials: AS
authors.lastname: Schulz
authors.affiliation: Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, D-53127, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C110856:proteasome maturation protein; D000123:Acetyltransferases; C406825:MCM3AP protein, human
keywords: AID; GANP; MCM3AP; NF-κB; POMP; homologous recombination; immunodeficiency