title: Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24.
abstract: Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Daschkey
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany. kirsten.bienemann@med.uni-duesseldorf.de.
authors.forename: Kirsten
authors.identifier: 0000-0002-1450-1928
authors.initials: K
authors.lastname: Bienemann
authors.affiliation: Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Schuster
authors.affiliation: Children's Hospital, University of Würzburg, Würzburg, Germany.
authors.forename: Hans Wolfgang
authors.initials: HW
authors.lastname: Kreth
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: René Martin
authors.initials: RM
authors.lastname: Linka
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hönscheid
authors.affiliation: Insitute of Toxicology, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
authors.affiliation: Center for Medical Biotechnology, Biological Faculty, University Duisburg-Essen, Essen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Johannes
authors.affiliation: Virological Institute, Clinical and Molecular Virology, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleckenstein
authors.affiliation: Department of Gene Vectors, Helmholtz Center Munich, Munich, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Kempkes
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gombert
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
mesh_terms: D019943:Amino Acid Substitution; D002453:Cell Cycle; D003062:Codon; D003241:Consanguinity; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins; D017809:Fatal Outcome; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000175:diagnosis* / Q000235:genetics* / Q000821:virology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D035781:Siblings; D015398:Signal Transduction; D012854:Sister Chromatid Exchange; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination; D000073359:Exome Sequencing
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; C518296:FAAP24 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D011948:Receptors, Antigen, T-Cell
keywords: DNA repair defects; EBV; EBV-associated lymphoproliferation; FAAP24 deficiency; immunodeficiency