A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia
A transgenic mouse model demonstrates a dominant negative effect of a point mutation in the RPS19 gene associated with Diamond-Blackfan anemia
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DOI：
10.1182/blood-2010-03-275776
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发表时间：
2010-10-14
期刊：
影响因子：
20.3
通讯作者：
Bodine, David M.
中科院分区：
文献类型：
--
作者：
Devlin, Emily E.;DaCosta, Lydie;Bodine, David M.
钻石黑扇贫血(DBA)是一种遗传性红细胞减少症，与至少8个不同的核糖体蛋白基因突变有关。在大约25%的DBA家族中发现了编码核糖体蛋白S19(RPS19)的基因突变。这些突变中的大多数会扰乱RPS19蛋白的翻译或稳定性，并被预测会由于单倍体不足而导致DBA。然而，大约30%的RPS19突变是错义突变，不会改变RPS19蛋白的稳定性，并被假设为通过显性负机制起作用。为了正式验证这一假设，我们建立了一个表达RPS19突变的转基因小鼠模型，在该突变中，62密码子(RPS19R62W)的精氨酸残基被色氨酸残基取代。RPS19R62W在发育中的小鼠中的结构性表达是致命的。与DBA相似，RPS19R62W的条件性表达导致生长迟缓、轻度贫血、红系祖细胞数量减少，并显著抑制红系终末成熟。RNA图谱显示，700多个调控异常的基因属于DBA患者细胞RNA图谱中被破坏的相同途径。RPS19R62W是一个显性的DBA负性突变。(《血色》2010；116(15)：2826-2835)
Diamond Blackfan anemia (DBA) is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding ribosomal protein S19 (RPS19) have been identified in approximately 25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately 30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an arginine residue is replaced with a tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors, and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated more than 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. We conclude that RPS19R62W is a dominant negative DBA mutation. (Blood.2010;116(15):2826-2835)