Ribosomal Protein Genes RPS10 and RPS26 Are Commonly Mutated in Diamond-Blackfan Anemia
Ribosomal Protein Genes RPS10 and RPS26 Are Commonly Mutated in Diamond-Blackfan Anemia
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DOI：
10.1016/j.ajhg.2009.12.015
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发表时间：
2010-02-12
影响因子：
9.8
通讯作者：
Gazda, Hanna T.
中科院分区：
文献类型：
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作者：
Doherty, Leana;Sheen, Mee Rie;Gazda, Hanna T.
钻石-布莱克凡贫血(DBA)是一种遗传性骨髓衰竭综合征，其特征是贫血，通常在一岁生日之前或儿童早期出现，与出生缺陷和癌症风险增加有关。虽然贫血是DBA最显著的特征，但该病也以生长迟缓和先天性畸形为特征，特别是颅面、上肢、心脏和泌尿系统缺陷，约占30%-50%。在大约43%的患者中，DBA与七个核糖体蛋白(RP)基因RPS19、RPS24、RPS17、RPL35A、RPL5、RPL11和RPS7的突变有关。为了继续我们对DBA人群中RP基因的大规模筛选，我们在DBA患者群体中测序了35个核糖体蛋白基因，RPL15、RPL24、RPL29、RPL32、RPL34、RPL9、RPL37、RPS14、RPS23、RPL10A、RPS10、RPS12、RPS18、RPL30、RPS20、RPL12、RPL7A、RPS6、RPL27A、RPLP2、RPS25、RPS3、RPL41、RPL6、RPLP0、RPS26、RPL21、RPL36AL、RPS29、RPL4、RPLP1、RPL13、RPS15A、RPS2和RPL38。我们在5个先证者中发现了3个不同的RPS10突变，在12个先证者中发现了9个不同的RPS26突变。对携带RPS10和RPS26基因突变患者的淋巴母细胞进行的Pre-rRNA分析显示，18S-E Pre-RNA水平升高。这种积累与用siRNAs敲除RPS10或RIIS26表达后在HeLa细胞中观察到的表型一致，表明DBA患者RPS10和RPS26基因的突变影响了蛋白质在rRNA加工中的功能。
Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in similar to 30%-50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct Mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E prerRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RIIS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing.