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Association of clinical severity with FANCB variant type in Fanconi anemia
Blood ( IF 20.3 ) Pub Date : 2020-04-30 , DOI: 10.1182/blood.2019003249
Moonjung Jung 1 , Ramanagouda Ramanagoudr-Bhojappa 2 , Sylvie van Twest 3 , Rasim Ozgur Rosti 1 , Vincent Murphy 3 , Winnie Tan 3 , Frank X Donovan 2 , Francis P Lach 1 , Danielle C Kimble 2 , Caroline S Jiang 4 , Roger Vaughan 4 , Parinda A Mehta 5, 6 , Filomena Pierri 7 , Carlo Dufour 7 , Arleen D Auerbach 8 , Andrew J Deans 3 , Agata Smogorzewska 1 , Settara C Chandrasekharappa 2
Affiliation  

Fanconi anemia (FA) is the most common genetic cause of bone marrow failure, and is caused by inherited pathogenic variants in any of 22 genes. Of these, only FANCB is X-linked. We describe a cohort of 19 children with FANCB variants, from 16 families of the International Fanconi Anemia Registry (IFAR). Those with FANCB deletion or truncation demonstrate earlier than average onset of bone marrow failure, and more severe congenital abnormalities compared to a large series of FA individuals in the published reports. This reflects the indispensable role of FANCB protein in the enzymatic activation of FANCD2 monoubiquitination, an essential step in the repair of DNA interstrand crosslinks. For FANCB missense variants, more variable severity is associated with the extent of residual FANCD2 monoubiquitination activity. We used transcript analysis, genetic complementation, and biochemical reconstitution of FANCD2 monoubiquitination to determine the pathogenicity of each variant. Aberrant splicing and transcript destabilization were associated with two missense variants. Individuals carrying missense variants with drastically reduced FANCD2 monoubiquitination in biochemical and/or cell-based assays tended to show earlier onset of hematologic disease and shorter survival. Conversely, variants with near-normal FANCD2 monoubiquitination were associated with more favorable outcome. Our study reveals a genotype-phenotype correlation within the FA-B complementation group of FA, where severity associates with the level of residual FANCD2 monoubiquitination.

中文翻译:

范可尼贫血中临床严重程度与 FANCB 变异型的关联

范可尼贫血 (FA) 是骨髓衰竭最常见的遗传原因,由 22 种基因中任何一种的遗传性致病变异引起。其中,只有 FANCB 是 X-linked。我们描述了来自国际范可尼贫血登记处 (IFAR) 的 16 个家庭的 19 名 FANCB 变异儿童的队列。在已发表的报告中,与大量 FA 个体相比,FANCB 缺失或截断的患者比平均水平的骨髓衰竭发病更早,并且先天性异常更严重。这反映了 FANCB 蛋白在 FANCD2 单泛素化酶促激活中不可或缺的作用,FANCD2 单泛素化是修复 DNA 链间交联的必要步骤。对于 FANCB 错义变体,更多可变的严重性与残留 FANCD2 单泛素化活性的程度相关。我们使用了转录分析,FANCD2 单泛素化的遗传互补和生化重组以确定每个变体的致病性。异常剪接和转录不稳定与两种错义变体有关。在生化和/或基于细胞的分析中,携带 FANCD2 单泛素化显着降低的错义变体的个体往往表现出较早发病的血液疾病和较短的生存期。相反,具有接近正常 FANCD2 单泛素化的变异与更有利的结果相关。我们的研究揭示了 FA 的 FA-B 互补组内的基因型-表型相关性,其中严重程度与残留的 FANCD2 单泛素化水平相关。异常剪接和转录不稳定与两种错义变体有关。在生化和/或基于细胞的分析中,携带 FANCD2 单泛素化显着降低的错义变体的个体往往表现出较早发病的血液疾病和较短的生存期。相反,具有接近正常 FANCD2 单泛素化的变异与更有利的结果相关。我们的研究揭示了 FA 的 FA-B 互补组内的基因型-表型相关性,其中严重程度与残留的 FANCD2 单泛素化水平相关。异常剪接和转录不稳定与两种错义变体有关。在生化和/或基于细胞的分析中,携带 FANCD2 单泛素化显着降低的错义变体的个体往往表现出较早发病的血液疾病和较短的生存期。相反,具有接近正常 FANCD2 单泛素化的变异与更有利的结果相关。我们的研究揭示了 FA 的 FA-B 互补组内的基因型-表型相关性,其中严重程度与残留的 FANCD2 单泛素化水平相关。相反,具有接近正常 FANCD2 单泛素化的变异与更有利的结果相关。我们的研究揭示了 FA 的 FA-B 互补组内的基因型-表型相关性,其中严重程度与残留的 FANCD2 单泛素化水平相关。相反,具有接近正常 FANCD2 单泛素化的变异与更有利的结果相关。我们的研究揭示了 FA 的 FA-B 互补组内的基因型-表型相关性,其中严重程度与残留的 FANCD2 单泛素化水平相关。
更新日期:2020-04-30
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