Ribosomal Function and Diamond-Blackfan Anemia

描述(由申请人提供)： 钻石-黑粉贫血(DBA)是一种罕见的纯红细胞再生障碍性贫血，表现在婴儿早期。实际上，DBA的每一个方面都是不同的，对了解和治疗这种疾病的努力构成了相当大的挑战。大约25%的DBA病例与核糖体蛋白$19基因突变有关，而其余病例的病因不明。这项应用的一个目标是解决DBA的分子基础，重点是Rps19在核糖体合成中的作用。我们在酵母中的研究表明，Rps19是40S核糖体亚基成熟所必需的。我们计划扩大这些研究，并检查DBA患者细胞系中核糖体的合成。我们还鉴定了其他几种酵母核糖体蛋白，它们似乎在40S亚基的成熟过程中与Rps19合作。如果Rps19正常的患者在核糖体合成方面存在缺陷，编码与Rps19合作的蛋白质的基因将成为致病突变的候选基因。我们在酵母中的研究也指出，有必要对DBA患者的Rps19基因中确定的可能致病突变进行功能测试。最后，我们将在转基因小鼠模型中研究核糖体合成与骨髓衰竭的关系。本应用的具体目的是：1.继续研究DBA错义突变对酵母中Rps19蛋白功能的影响。2.确定DBA患者细胞系的蛋白质合成机制是否存在缺陷。3.确定哪些核糖体蛋白依赖于Rps19组装成40S核糖体亚基。4.研究LAMR1基因半合子小鼠的表型特征，包括血液学分析、肿瘤发病率、是否存在其他先天异常。

DESCRIPTION (provided by applicant): Diamond-Blackfan anemia (DBA) is a rare pure red-cell aplasia that presents early in infancy. Virtually every aspect of DBA is heterogeneous, posing considerable challenges to efforts to understand and treat this disease. Approximately 25% of DBA cases are linked to mutations in the ribosomal protein $19 gene, whereas the remaining cases are of unknown etiology. A goal of this application is to address the molecular basis of DBA, focusing on the role of Rps19 in ribosome synthesis. Our studies in yeast have shown that Rps19 is required for the maturation of 40S ribosomal subunits. We plan to extend these studies and examine ribosome synthesis in cell lines from DBA patients. We have also identified several other yeast ribosomal proteins that appear to cooperate with Rps19 in the maturation of 40S subunits. If patients with normal Rps19 were defective in ribosome synthesis, genes encoding proteins that cooperate with Rps19 would become candidate genes for disease-causing mutations. Our studies in yeast have also pointed to a need for functional testing of putative disease-causing mutations identified in Rps19 genes from DBA patients. Finally, we will study the relationship between ribosome synthesis and bone marrow failure in a transgenic mouse model. The specific aims of this application are to: 1. continue studies characterizing the effect of DBA missense mutations on the function of the Rps19 protein in yeast. 2. determine if there are defects in the protein synthetic machinery in cell lines from DBA patients. 3. determine which ribosomal proteins depend on Rps19 for their assembly into 40S ribosomal subunits. 4. characterize the phenotype of mice hemizygous for LAMR1 including hematological analysis, cancer incidence, and the presence of other congenital abnormalities.