Hematology Unit, Pediatric Department, University of Torino Piazza Polonia 94, 10126 Torino, Italy.
Haematologica. 2010 Feb;95(2):206-13. doi: 10.3324/haematol.2009.011783. Epub 2009 Sep 22.
Diamond-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.
In 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.
About 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.
Mutations 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.
Diamond-Blackfan 贫血是一种罕见的儿童纯红细胞再生障碍性贫血，由于红系祖细胞的内在缺陷所致。约 40%的患者存在各种畸形。50%以上的病例用类固醇治疗可纠正贫血；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。少数患者描述的 RPS24、RPS17 和 RPL35A 突变表明 Diamond-Blackfan 贫血是核糖体生物发生的一种疾病。两个新基因（RPL5、RPL11），编码核糖体大亚基的核糖体蛋白，据报道在相当一部分患者中涉及。
在这项基因型-表型分析中，我们对 92 名意大利 Diamond-Blackfan 贫血患者进行了 RPS14、RPS16、RPS24、RPL5、RPL11 和 RPL35A 的编码序列和内含子-外显子边界的筛选，这些患者的 RPS19 突变均为阴性。
筛查的患者中约 20%有 RPL5 或 RPL11 突变，仅有 1.6%有 RPS24 突变。除了我们在此报告的三个突变外，其余都是新突变。在 RPS14、RPS16 或 RPL35A 中未发现突变。值得注意的是，我们观察到 RPL5 和 RPL11 突变患者的躯体畸形比例较高。RPL5 突变与颅面畸形密切相关，而手部畸形与 RPL11 突变密切相关。
在意大利 Diamond-Blackfan 贫血患者中，约有 50%的病例与四个核糖体蛋白的突变有关。基因型-表型数据表明，在有畸形的 Diamond-Blackfan 贫血患者中，应首先对 RPL5 和 RPL11 进行突变筛查。
