Wang RuNan, Yoshida Kenichi, Toki Tsutomu, Sawada Takafumi, Uechi Tamayo, Okuno Yusuke, Sato-Otsubo Aiko, Kudo Kazuko, Kamimaki Isamu, Kanezaki Rika, Shiraishi Yuichi, Chiba Kenichi, Tanaka Hiroko, Terui Kiminori, Sato Tomohiko, Iribe Yuji, Ohga Shouichi, Kuramitsu Madoka, Hamaguchi Isao, Ohara Akira, Hara Junichi, Goi Kumiko, Matsubara Kousaku, Koike Kenichi, Ishiguro Akira, Okamoto Yasuhiro, Watanabe Kenichiro, Kanno Hitoshi, Kojima Seiji, Miyano Satoru, Kenmochi Naoya, Ogawa Seishi, Ito Etsuro
Department of Paediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Br J Haematol. 2015 Mar;168(6):854-64. doi: 10.1111/bjh.13229. Epub 2014 Nov 25.
Diamond-Blackfan anaemia is a congenital bone marrow failure syndrome that is characterized by red blood cell aplasia. The disease has been associated with mutations or large deletions in 11 ribosomal protein genes including RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS29, RPL5, RPL11, RPL26 and RPL35A as well as GATA1 in more than 50% of patients. However, the molecular aetiology of many Diamond-Blackfan anaemia cases remains to be uncovered. To identify new mutations responsible for Diamond-Blackfan anaemia, we performed whole-exome sequencing analysis of 48 patients with no documented mutations/deletions involving known Diamond-Blackfan anaemia genes except for RPS7, RPL26, RPS29 and GATA1. Here, we identified a de novo splicing error mutation in RPL27 and frameshift deletion in RPS27 in sporadic patients with Diamond-Blackfan anaemia. In vitro knockdown of gene expression disturbed pre-ribosomal RNA processing. Zebrafish models of rpl27 and rps27 mutations showed impairments of erythrocyte production and tail and/or brain development. Additional novel mutations were found in eight patients, including RPL3L, RPL6, RPL7L1T, RPL8, RPL13, RPL14, RPL18A and RPL31. In conclusion, we identified novel germline mutations of two ribosomal protein genes responsible for Diamond-Blackfan anaemia, further confirming the concept that mutations in ribosomal protein genes lead to Diamond-Blackfan anaemia.
先天性纯红细胞再生障碍性贫血是一种先天性骨髓衰竭综合征，其特征为红细胞发育不全。超过50%的患者中，该疾病与11种核糖体蛋白基因（包括RPS7、RPS10、RPS17、RPS19、RPS24、RPS26、RPS29、RPL5、RPL11、RPL26和RPL35A）以及GATA1的突变或大片段缺失有关。然而，许多先天性纯红细胞再生障碍性贫血病例的分子病因仍有待揭示。为了鉴定导致先天性纯红细胞再生障碍性贫血的新突变，我们对48例患者进行了全外显子组测序分析，这些患者除RPS7、RPL26、RPS29和GATA1外，未记录到涉及已知先天性纯红细胞再生障碍性贫血基因的突变/缺失。在此，我们在散发性先天性纯红细胞再生障碍性贫血患者中鉴定出RPL27的一个新生剪接错误突变和RPS27的移码缺失。基因表达的体外敲低扰乱了核糖体前体RNA加工。rpl27和rps27突变的斑马鱼模型显示红细胞生成以及尾巴和/或大脑发育受损。在8例患者中发现了其他新突变，包括RPL3L、RPL6、RPL7L1T、RPL8、RPL13、RPL14、RPL18A和RPL31。总之，我们鉴定出了导致先天性纯红细胞再生障碍性贫血的两个核糖体蛋白基因的新种系突变，进一步证实了核糖体蛋白基因突变导致先天性纯红细胞再生障碍性贫血这一概念。
