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 Lewis & 12 others Michael 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, Helmut Hanenberg

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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.

Original languageEnglish
Pages (from-to)5093-5108
Number of pages16
JournalHuman Molecular Genetics
Volume24
Issue number18
Early online date17 Jun 2015
DOIs
Publication statusPublished - 15 Sep 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

Keywords

  • 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

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. 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 M. ; Honisch, Ellen ; Niederacher, Dieter ; Chakraborty, Sujata C. ; Vance, Gail H. ; 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.",
keywords = "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",
author = "Virts, {Elizabeth L.} and Anna Jankowska and Craig Mackay and Glaas, {Marcel F.} and Constanze Wiek and Kelich, {Stephanie L.} and Nadine Lottmann and Kennedy, {Felicia M.} and Christophe Marchal and Erik Lehnert and Scharf, {R{\"u}diger E.} and Carlo Dufour and Marina Lanciotti and Piero Farruggia and Alessandra Santoro and S{\"u}reyya Savasan and Kathrin Scheckenbach and J{\"o}rg Schipper and Martin Wagenmann and Todd Lewis and Michael Leffak and Farlow, {Janice L.} and Foroud, {Tatiana M.} and Ellen Honisch and Dieter Niederacher and Chakraborty, {Sujata C.} and Vance, {Gail H.} and Dmitry Pruss and Timms, {Kirsten M.} and Lanchbury, {Jerry S.} and Alpi, {Arno F.} and Helmut Hanenberg",
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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, TM, Honisch, E, Niederacher, D, Chakraborty, SC, Vance, GH, 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, pp. 5093-5108. 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 M.; Honisch, Ellen; Niederacher, Dieter; Chakraborty, Sujata C.; Vance, Gail H.; Pruss, Dmitry; Timms, Kirsten M.; Lanchbury, Jerry S.; Alpi, Arno F. (Lead / Corresponding author); Hanenberg, Helmut (Lead / Corresponding author).

In: Human Molecular Genetics, Vol. 24, No. 18, 15.09.2015, p. 5093-5108.

Research output: Contribution to journalArticle

TY - JOUR

T1 - AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia

AU - Virts, Elizabeth L.

AU - Jankowska, Anna

AU - Mackay, Craig

AU - Glaas, Marcel F.

AU - Wiek, Constanze

AU - Kelich, Stephanie L.

AU - Lottmann, Nadine

AU - Kennedy, Felicia M.

AU - Marchal, Christophe

AU - Lehnert, Erik

AU - Scharf, Rüdiger E.

AU - Dufour, Carlo

AU - Lanciotti, Marina

AU - Farruggia, Piero

AU - Santoro, Alessandra

AU - Savasan, Süreyya

AU - Scheckenbach, Kathrin

AU - Schipper, Jörg

AU - Wagenmann, Martin

AU - Lewis, Todd

AU - Leffak, Michael

AU - Farlow, Janice L.

AU - Foroud, Tatiana M.

AU - Honisch, Ellen

AU - Niederacher, Dieter

AU - Chakraborty, Sujata C.

AU - Vance, Gail H.

AU - Pruss, Dmitry

AU - Timms, Kirsten M.

AU - Lanchbury, Jerry S.

AU - Alpi, Arno F.

AU - Hanenberg, Helmut

N1 - © The Author 2015. Published by Oxford University Press.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Alleles

KW - Breast neoplasms

KW - Child

KW - Child, Preschool

KW - Chromosome breakage

KW - DNA damage

KW - Exons

KW - Fanconi anemia

KW - Fanconi anemia complementation group D2 protein

KW - Female

KW - Fibroblasts

KW - Gene deletion

KW - Gene duplication

KW - Gene knockout techniques

KW - Genetic complementation test

KW - Germ cells

KW - Germ-line mutation

KW - Humans

KW - Male

KW - Middle aged

KW - Nonsense mediated mRNA decay

KW - Phenotype

KW - RNA, Messenger

KW - Stem cells

KW - Ubiquitin-conjugating enzymes

KW - Ubiquitination

U2 - 10.1093/hmg/ddv227

DO - 10.1093/hmg/ddv227

M3 - Article

VL - 24

SP - 5093

EP - 5108

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 18

ER -