Abstract：
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease caused by mutation in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. SDS has a variety of clinical features, including exocrine pancreatic insufficiency and hematological dysfunction. Neutropenia is the most common symptom in patients with SDS. SDS is also associated with an elevated risk of developing myelodysplastic syndromes and acute myeloid leukemia. The SBDS protein is involved in ribosome biogenesis, ribosomal RNA metabolism, stabilization of mitotic spindles and cellular stress responses, yet the function of SBDS in detail is still incompletely understood. Considering the diverse function of SBDS, the effect of SBDS seems to be different in different cells and tissues. In this study, we established myeloid cell line 32Dcl3 with a common pathogenic SBDS variant on both alleles in intron 2, 258 + 2T > C, and examined the cellular damage that resulted. We found that the protein synthesis was markedly decreased in the mutant cells. Furthermore, reactive oxygen species (ROS) production was increased, and oxidation of the mitochondrial membrane lipids and DNA damage were induced. These findings provide new insights into the cellular and molecular pathology caused by SBDS deficiency in myeloid cells.
摘要：
Shwachman-Diamond综合征（SDS）是由Shwachman-Bodian-Diamond综合征（SBDS）基因突变引起的常染色体隐性遗传疾病。SDS具有多种临床特点，包括胰腺外分泌功能不全和血液学功能障碍。中性粒细胞减少症是SDS患者最常见的症状。SDS还与发生骨髓增生异常综合征和急性髓细胞性白血病的风险升高有关。SBDS蛋白参与核糖体生物发生，核糖体RNA代谢，稳定有丝分裂纺锤体和细胞应激反应，然而，SBDS的功能仍未被完全理解。考虑到SBDS的多种功能，SBDS在不同的细胞和组织中的作用似乎不同。在这项研究中,我们建立了髓系细胞系32Dcl3，在内含子2中的两个等位基因上具有常见的致病性SBDS变体，258+2T>C，并检查了由此导致的细胞损伤。我们发现突变细胞中的蛋白质合成显着降低。此外，活性氧（ROS）的产生增加，并诱导线粒体膜脂质氧化和DNA损伤。这些发现为骨髓细胞中SBDS缺乏引起的细胞和分子病理学提供了新的见解。
