Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia
Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia
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DOI：
10.1182/blood-2008-02-140012
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Areci, Robert J.
中科院分区：
文献类型：
--
作者：
Farrar, Jason E.;Nater, Michelle;Areci, Robert J.
Diamond-Blackfan贫血（DBA）是一种遗传性骨髓衰竭综合征，以贫血、先天性异常和癌症易感性为特征。核糖体小亚基基因RPS 19、RPS 24和RPS 17在大约三分之一的患者中发生突变。我们采用高分辨率基因组定位和基因表达微阵列相结合的候选基因策略，对2例染色体3q缺失的DBA患者进行分析，以确定RPL 35 A为潜在的DBA基因。DBA先证者队列的序列分析证实DBA中涉及RPL 35 A。shRNA抑制表明Rp 135 a对于28 S和5.8S rRNA的成熟、60 S亚基生物合成、正常增殖和细胞存活是必需的。在原代DBA淋巴母细胞系中的前rRNA加工分析表明，在RPL 35 A突变型和一些RPL 35 A野生型患者中，核糖体大亚基rRNA的改变相似，这表明在某些DBA病例中可能存在额外的核糖体大亚基基因缺陷。这些数据表明，核糖体大亚基蛋白的改变引起DBA，并支持DBA主要是核糖体功能改变的结果的假设。研究结果还证实，核糖体大亚基蛋白的单倍不足导致骨髓衰竭和潜在的癌症易感性。
Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rp135a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.