Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations
Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations
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DOI：
10.3324/haematol.2009.011783
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发表时间：
2010-02-01
期刊：
影响因子：
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通讯作者：
Ramenghi, Ugo
中科院分区：
文献类型：
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作者：
Quarello, Paola;Garelli, Emanuela;Ramenghi, Ugo
背景钻石-布莱克范贫血是一种罕见的纯红细胞再生障碍性儿童贫血，由红细胞生成祖细胞的内在缺陷所致。约40%的患者表现出各种畸形。超过 50% 的病例可通过类固醇治疗纠正贫血；无反应者需要长期输血或干细胞移植。编码核糖体蛋白 S19 的 RPS19 基因缺陷是 Diamond-Blackfan 贫血的主要已知原因，占病例的 25% 以上。少数患者中描述的 RPS24、RPS17 和 RPL35A 突变表明 Diamond-Blackfan 贫血是一种核糖体生物发生障碍。据报道，编码大亚基核糖体蛋白的两个新基因（RPL5、RPL11）与相当大比例的患者有关。设计和方法在该基因型-表型分析中，我们筛选了 92 名意大利患者的 RPS14、RPS16、RPS24、RPL5、RPL11 和 RPL35A 的编码序列和内含子-外显子边界。 RPS19 突变阴性的 Diamond-Blackfan 贫血患者。结果 大约 20% 的筛查患者存在 RPL5 或 RPL11 突变，只有 1.6% 存在 RPS24 突变。我们在这里报告的除了三个突变之外的所有突变都是新突变。 RPS14、RPS16未发现突变；或RPL35A。值得注意的是，我们观察到 RPL5 和 RPL11 突变患者的体细胞畸形比例较高。 RPL5 突变与颅面畸形之间以及手部畸形与 RPL11 突变之间存在明显的密切关联。结论四种核糖体蛋白突变约占意大利患者所有 Diamond-Blackfan 贫血病例的 50%。基因型-表型数据表明，对于患有畸形的 Diamond-Blackfan 贫血患者，突变筛查应从 RPL5 和 RPL11 开始。
BackgroundDiamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50%, of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients.Design and MethodsIn this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations.ResultsAbout 20%, of the patients screened had mutations in RPL5 or RPL11, and only 1.6%, in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16; or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations.ConclusionsMutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.