title: AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia.
abstract: Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.
authors.affiliation: Department of Pediatrics and.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Virts
authors.affiliation: Department of Pediatrics and.
authors.forename: Anna
authors.initials: A
authors.lastname: Jankowska
authors.affiliation: Department of MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Mackay
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Glaas
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Constanze
authors.initials: C
authors.lastname: Wiek
authors.affiliation: Department of Pediatrics and.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Kelich
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Nadine
authors.initials: N
authors.lastname: Lottmann
authors.affiliation: Department of Pediatrics and.
authors.forename: Felicia M
authors.initials: FM
authors.lastname: Kennedy
authors.affiliation: Department of Pediatrics and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marchal
authors.affiliation: Department of Experimental and Clinical Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Lehnert
authors.affiliation: Department of Experimental and Clinical Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Rüdiger E
authors.initials: RE
authors.lastname: Scharf
authors.affiliation: Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dufour
authors.affiliation: Hematology Unit, G. Gaslini Children's Hospital, Genoa, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Lanciotti
authors.affiliation: Pediatric Hematology and Oncology Unit, A.R.N.A.S. Ospedale Civico, Palermo, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Farruggia
authors.affiliation: A.O. Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Süreyya
authors.initials: S
authors.lastname: Savasan
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Scheckenbach
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schipper
authors.affiliation: Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and.
authors.forename: Martin
authors.initials: M
authors.lastname: Wagenmann
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Lewis
authors.affiliation: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH 45435, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Leffak
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Farlow
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Department of Gynecology, Heinrich Heine University, Düsseldorf, Germany and.
authors.forename: Ellen
authors.initials: E
authors.lastname: Honisch
authors.affiliation: Department of Gynecology, Heinrich Heine University, Düsseldorf, Germany and.
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Sujata C
authors.initials: SC
authors.lastname: Chakraborty
authors.affiliation: Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Gail H
authors.initials: GH
authors.lastname: Vance
authors.affiliation: Myriad Genetics Inc., Salt Lake City, UT, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pruss
authors.affiliation: Myriad Genetics Inc., Salt Lake City, UT, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Timms
authors.affiliation: Myriad Genetics Inc., Salt Lake City, UT, USA.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Lanchbury
authors.affiliation: Department of MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK, hhanenbe@iu.edu a.f.alpi@dundee.ac.uk.
authors.forename: Arno F
authors.initials: AF
authors.lastname: Alpi
authors.affiliation: Department of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA, Department of Otorhinolaryngology and Head/Neck Surgery (ENT) and hhanenbe@iu.edu a.f.alpi@dundee.ac.uk.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019457:Chromosome Breakage; D004249:DNA Damage; D005091:Exons; D005199:Fanconi Anemia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D020440:Gene Duplication; D055786:Gene Knockout Techniques; D005816:Genetic Complementation Test; D005854:Germ Cells / Q000378:metabolism*; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D059365:Nonsense Mediated mRNA Decay; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; C513404:UBE2T protein, human; D044763:Ubiquitin-Conjugating Enzymes