AluY-mediated Germline Deletion, Duplication and Somatic Stem Cell Reversion in UBE2T Defines a New Subtype of Fanconi Anemia

摘要: 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 associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known genes assemble E3 ligase complex, which catalyzes monoubiquitination FANCD2 essential for replicative DNA crosslink repair. Here, we identify first patient biallelic germline mutations in ubiquitin E2 conjugase UBE2T. Both were aluY-mediated: paternal deletion maternal duplication exons 2–6. These loss-of-function UBE2T induced phenotype similar defects early absence monoubiquitination. The produced mutant mRNA that could encode functional protein but was degraded nonsense-mediated decay. In patient's hematopoietic stem cells, allele 2–6 spontaneously reverted wild-type monoallelic recombination at duplicated aluY repeat, thereby preventing failure. Analysis 814 normal individuals 850 breast patients or identified only two controls, suggesting aluY-mediated recombinations within locus are not an increased risk. Finally, mutation detected high-risk BRCA1/2. Cumulatively, as bona fide gene (FANCT) also may be susceptibility gene.