AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia

Elizabeth L. Virts, Anna Jankowska, Craig Mackay, Marcel F. Glaas, Constanze Wiek, Stephanie L. Kelich, Nadine Lottmann, Felicia M. Kennedy, Christophe Marchal, Erik Lehnert, Rüdiger E. Scharf, Carlo Dufour, Marina Lanciotti, Piero Farruggia, Alessandra Santoro, Süreyya Savasan, Kathrin Scheckenbach, Jörg Schipper, Martin Wagenmann, Todd LewisMichael Leffak, Janice L. Farlow, Tatiana M. Foroud, Ellen Honisch, Dieter Niederacher, Sujata C. Chakraborty, Gail H. Vance, Dmitry Pruss, Kirsten M. Timms, Jerry S. Lanchbury, Arno F. Alpi (Lead / Corresponding author), Helmut Hanenberg (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)5093-5108
Number of pages16
JournalHuman Molecular Genetics
Issue number18
Early online date17 Jun 2015
Publication statusPublished - 15 Sept 2015


  • Adolescent
  • Adult
  • Alleles
  • Breast neoplasms
  • Child
  • Child, Preschool
  • Chromosome breakage
  • DNA damage
  • Exons
  • Fanconi anemia
  • Fanconi anemia complementation group D2 protein
  • Female
  • Fibroblasts
  • Gene deletion
  • Gene duplication
  • Gene knockout techniques
  • Genetic complementation test
  • Germ cells
  • Germ-line mutation
  • Humans
  • Male
  • Middle aged
  • Nonsense mediated mRNA decay
  • Phenotype
  • RNA, Messenger
  • Stem cells
  • Ubiquitin-conjugating enzymes
  • Ubiquitination


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