MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child.
Hum Mutat
; 37(3): 257-68, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26615982
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acetiltransferases
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Dano ao DNA
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Chaperonas Moleculares
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Peptídeos e Proteínas de Sinalização Intracelular
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Reparo do DNA
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Síndromes de Imunodeficiência
Limite:
Humans
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Alemanha