MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child

Hum Mutat. 2016 Mar;37(3):257-68. doi: 10.1002/humu.22939. Epub 2015 Dec 30.

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.

Keywords: AID; GANP; MCM3AP; NF-κB; POMP; homologous recombination; immunodeficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / genetics*
  • DNA Damage / genetics*
  • DNA Damage / physiology
  • DNA Repair / genetics*
  • DNA Repair / physiology
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Molecular Chaperones / genetics*
  • Mutation / genetics
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • proteasome maturation protein
  • Acetyltransferases
  • MCM3AP protein, human