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 Foroud, Ellen Honisch, Dieter Niederacher, Sujata C. Chakraborty, Gail Vance, Dmitry Pruss, Kirsten M. Timms, Jerry S. Lanchbury, Arno F. Alpi, Helmut Hanenberg

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Article numberddv227
Pages (from-to)5093-5108
Number of pages16
JournalHuman Molecular Genetics
Volume24
Issue number18
DOIs
StatePublished - Apr 9 2015

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Fanconi Anemia
Adult Stem Cells
Exons
Germ-Line Mutation
Mothers
Breast Neoplasms
Genetic Recombination
gamma-Glutamyl Hydrolase
Bone Marrow
Nonsense Mediated mRNA Decay
Alleles
Genes
Bone Neoplasms
Mutation
Ubiquitin-Protein Ligases
Neoplasm Genes
DNA
Mutagens
Hematopoietic Stem Cells
Ubiquitin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Virts, E. L., Jankowska, A., Mackay, C., Glaas, M. F., Wiek, C., Kelich, S. L., ... Hanenberg, H. (2015). AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. Human Molecular Genetics, 24(18), 5093-5108. [ddv227]. https://doi.org/10.1093/hmg/ddv227

AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. / Virts, Elizabeth L.; Jankowska, Anna; Mackay, Craig; Glaas, Marcel F.; Wiek, Constanze; Kelich, Stephanie L.; Lottmann, Nadine; Kennedy, Felicia M.; Marchal, Christophe; Lehnert, Erik; Scharf, Rüdiger E.; Dufour, Carlo; Lanciotti, Marina; Farruggia, Piero; Santoro, Alessandra; Savasan, Süreyya; Scheckenbach, Kathrin; Schipper, Jörg; Wagenmann, Martin; Lewis, Todd; Leffak, Michael; Farlow, Janice L.; Foroud, Tatiana; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C.; Vance, Gail; Pruss, Dmitry; Timms, Kirsten M.; Lanchbury, Jerry S.; Alpi, Arno F.; Hanenberg, Helmut.

In: Human Molecular Genetics, Vol. 24, No. 18, ddv227, 09.04.2015, p. 5093-5108.

Research output: Contribution to journalArticle

Virts, EL, Jankowska, A, Mackay, C, Glaas, MF, Wiek, C, Kelich, SL, Lottmann, N, Kennedy, FM, Marchal, C, Lehnert, E, Scharf, RE, Dufour, C, Lanciotti, M, Farruggia, P, Santoro, A, Savasan, S, Scheckenbach, K, Schipper, J, Wagenmann, M, Lewis, T, Leffak, M, Farlow, JL, Foroud, T, Honisch, E, Niederacher, D, Chakraborty, SC, Vance, G, Pruss, D, Timms, KM, Lanchbury, JS, Alpi, AF & Hanenberg, H 2015, 'AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia', Human Molecular Genetics, vol. 24, no. 18, ddv227, pp. 5093-5108. https://doi.org/10.1093/hmg/ddv227
Virts, Elizabeth L. ; Jankowska, Anna ; Mackay, Craig ; Glaas, Marcel F. ; Wiek, Constanze ; Kelich, Stephanie L. ; Lottmann, Nadine ; Kennedy, Felicia M. ; Marchal, Christophe ; Lehnert, Erik ; Scharf, Rüdiger E. ; Dufour, Carlo ; Lanciotti, Marina ; Farruggia, Piero ; Santoro, Alessandra ; Savasan, Süreyya ; Scheckenbach, Kathrin ; Schipper, Jörg ; Wagenmann, Martin ; Lewis, Todd ; Leffak, Michael ; Farlow, Janice L. ; Foroud, Tatiana ; Honisch, Ellen ; Niederacher, Dieter ; Chakraborty, Sujata C. ; Vance, Gail ; Pruss, Dmitry ; Timms, Kirsten M. ; Lanchbury, Jerry S. ; Alpi, Arno F. ; Hanenberg, Helmut. / AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 18. pp. 5093-5108.
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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.",
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AU - Lottmann, Nadine

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