PDF(Pubmed)
Abstract：
Diamond-Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated.
摘要：
Diamond-Blackfan贫血（DBA）是一种以骨髓红细胞发育不全为特征的核糖体病，通常在生命的头几个月内出现严重的贫血。DBA通常归因于核糖体蛋白(RP)基因中的杂合突变以及核糖体RNA(rRNA)成熟或水平的缺陷。除了经典的DBA,DBA样疾病已被描述为16个基因的变异（主要在GATA1中，其次是ADA2别名CECR1，HEATR3和TSR2）。迄今为止,在RP基因中已经报道了一千多个变异。剪接变异占DBA中可识别的遗传缺陷的6%，当关注致病性和可能的致病性（P/LP）变异时，其患病率为14.3％，从而突出了这种改变对RP翻译的影响，随后,在核糖体水平。我们在此介绍了两个在RPS17和RPS26中具有新的致病性剪接变体的病例。讨论了DBA相关变体与特定表型特征和恶性肿瘤的关联以及每个DBA相关基因的致病变异的分子后果。自发缓解的决定因素，癌症发展，家族之间相同变体的可变表达，和RP缺陷对红系谱系的选择性仍有待阐明。
