Ribosomal Protein L5 and L11 Mutations Are Associated with Cleft Palate and Abnormal Thumbs in Diamond-Blackfan Anemia Patients
Ribosomal Protein L5 and L11 Mutations Are Associated with Cleft Palate and Abnormal Thumbs in Diamond-Blackfan Anemia Patients
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DOI：
10.1016/j.ajhg.2008.11.004
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发表时间：
2008-12-12
影响因子：
9.8
通讯作者：
Beggs, Alan H.
中科院分区：
文献类型：
--
作者：
Gazda, Hanna T.;Sheen, Mee Rie;Beggs, Alan H.
钻石-黑粉贫血(DBA)是一种先天性骨髓衰竭综合征，以红细胞再生障碍性贫血、大细胞性贫血、临床异质性和恶性风险增加为特征。虽然贫血是DBA最突出的特征，但该病也以生长迟缓和先天性异常为特征，类似于30%-50%的患者。在大约30%的患者中，这种疾病与四个核糖体蛋白(RP)基因RPS19、RPS24、RPS17和RPL35A的突变有关。然而，其余70%的病例的遗传基础仍不清楚。在这里，我们报告了RPS17的第二个已知突变，以及另外三个RP基因RPL5、RPL11和RPS7的可能致病突变。此外，我们在其他三个基因RPL36、RPS15和RPS27A中发现了意义未知的罕见变异。值得注意的是，仔细审查临床数据显示，RFL5的突变与多种身体异常有关，包括头面部、拇指和心脏异常，而孤立的拇指畸形主要存在于携带RPL11突变的患者中。我们还证明了DBA细胞中RPL5、RPL11或RPS7的突变与大或小核糖体亚单位产生途径中核糖体RNA成熟的不同缺陷有关，从而扩大了与DBA相关的核糖体RNA加工缺陷的谱系。
Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in similar to 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RFL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.