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.

Highlights

  • Fanconi anemia (FA) is an autosomal or X-linked recessive inherited DNA instability disorder that is caused by germline mutations in at least 17 genes (FANCA, FANCB, FANCC, FANCD1/ BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4 and FANCS/BRCA1) that are involved in the DNA damage response [1,2,3,4]

  • Within the first week of life, he was diagnosed as being affected by FA due to high levels of DEB-induced high chromosomal breakage in metaphases of hematopoietic cells: baseline 0.1 and 5.8 breaks/cell in the absence or presence of 0.1 μg/ml DEB

  • A facial appearance atypical for FA, normal bone marrow cellularity, normal leukocyte and thrombocyte counts after the perinatal period, mild anemia with a low mean corpuscular volume (Supplementary Material, Fig. S1) due to a thalassaemia minor mutation inherited from his father, and the failure to identify germline mutations in DNA repair genes prevented a clear genetic diagnosis for the first 16 years of his life

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Summary

Introduction

Fanconi anemia (FA) is an autosomal or X-linked recessive inherited DNA instability disorder that is caused by germline mutations in at least 17 genes (FANCA, FANCB, FANCC, FANCD1/ BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4 and FANCS/BRCA1) that are involved in the DNA damage response [1,2,3,4]. As FANCA, FANCC and FANCG are the most frequently mutated FA genes [5,9,11], the onset of bone marrow failure might differ in FA patients with rarer gene defects [2,4,12,13,14,15]. If bone marrow failure does not occur due to the presence of a ‘milder’ mutation with residual protein function or due to mosaicism in the hematopoietic system as a consequence of a gain-of-function mutation in hematopoietic stem cells [16,17,18,19], the diagnosis of FA is often made upon presentation with cancer or with severe toxicity after treatment of a malignancy with chemotherapy [5,20,21]

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