Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115, USA.
Am J Hum Genet. 2010 Feb 12;86(2):222-8. doi: 10.1016/j.ajhg.2009.12.015. Epub 2010 Jan 28.
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 approximately 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 pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 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.
Diamond-Blackfan 贫血（DBA）是一种遗传性骨髓衰竭综合征，其特征为贫血，通常在一岁前或幼儿期出现，与出生缺陷和癌症风险增加有关。虽然贫血是 DBA 最突出的特征，但该疾病还表现为生长迟缓以及先天性畸形，特别是颅面、上肢、心脏和泌尿系统缺陷，约 30%-50%的患者存在这些缺陷。DBA 与七个核糖体蛋白（RP）基因的突变有关，包括 RPS19、RPS24、RPS17、RPL35A、RPL5、RPL11 和 RPS7，约 43%的患者存在这些突变。为了继续在 DBA 人群中进行大规模的 RP 基因筛查，我们对 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）进行了测序，这些基因存在于我们的 117 名先证者 DBA 患者队列中。我们在 5 名先证者中发现了 RPS10 的三个不同突变，在 12 名先证者中发现了 RPS26 的九个不同突变。携带 RPS10 和 RPS26 突变的患者的淋巴母细胞系中的 pre-rRNA 分析显示 18S-E pre-rRNA 水平升高。这种积累与 HeLa 细胞中 RPS10 或 RPS26 表达被 siRNA 敲低后的表型观察结果一致，这表明 DBA 患者的 RPS10 和 RPS26 基因突变影响了 rRNA 加工中蛋白质的功能。
