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MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child.
Gatz, Susanne A; Salles, Daniela; Jacobsen, Eva-Maria; Dörk, Thilo; Rausch, Tobias; Aydin, Sevtap; Surowy, Harald; Volcic, Meta; Vogel, Walther; Debatin, Klaus-Michael; Stütz, Adrian M; Schwarz, Klaus; Pannicke, Ulrich; Hess, Timo; Korbel, Jan O; Schulz, Ansgar S; Schumacher, Johannes; Wiesmüller, Lisa.
Afiliação
  • Gatz SA; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
  • Salles D; Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
  • Jacobsen EM; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
  • Dörk T; Gynecology Research Unit, Hannover Medical School, Hannover, D-30625, Germany.
  • Rausch T; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
  • Aydin S; Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
  • Surowy H; Department of Human Genetics, Ulm University, Ulm, D-89081, Germany.
  • Volcic M; Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
  • Vogel W; Department of Human Genetics, Ulm University, Ulm, D-89081, Germany.
  • Debatin KM; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
  • Stütz AM; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
  • Schwarz K; 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.
  • Pannicke U; 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.
  • Hess T; Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, D-53127, Germany.
  • Korbel JO; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, D-69117, Germany.
  • Schulz AS; Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, D-89075, Germany.
  • Schumacher J; Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, D-53127, Germany.
  • Wiesmüller L; Department of Obstetrics and Gynecology, Ulm University, Ulm, D-89075, Germany.
Hum Mutat ; 37(3): 257-68, 2016 Mar.
Article em En | MEDLINE | ID: mdl-26615982
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Acetiltransferases / Dano ao DNA / Chaperonas Moleculares / Peptídeos e Proteínas de Sinalização Intracelular / Reparo do DNA / Síndromes de Imunodeficiência Idioma: En Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Acetiltransferases / Dano ao DNA / Chaperonas Moleculares / Peptídeos e Proteínas de Sinalização Intracelular / Reparo do DNA / Síndromes de Imunodeficiência Idioma: En Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Alemanha