Characterization of SMARCAL1:its expression/interactors

描述(申请人提供)：Schimke免疫性骨发育不良(SIOD)是一种常染色体隐性遗传性脊柱-骨骺发育不良症，其特征是1)身材矮小，伴有色素沉着和面部特征异常，2)蛋白尿，进行性肾功能衰竭，3)淋巴细胞减少，细胞免疫功能缺陷。此外，SIOD患者甲状腺功能障碍、骨髓发育不良、眼部异常和脑缺血的发生率较高。进展性肾功能衰竭、免疫缺陷、骨髓发育不良和脑缺血可导致严重的发病率和死亡率。透析和肾移植是治疗进展性肾功能衰竭的唯一有效方法，骨髓移植是治疗血细胞减少症的唯一有效方法。对于生长障碍和脑缺血，目前还没有有效的治疗方法。在过去的5年里，我收集了26个家庭的SIOD患者的DNA样本和临床信息。利用其中父母血缘关系密切的四个家庭，我最近完成了全基因组筛查，并将siod定位在染色体2q34-q35上。随后，通过候选基因方法，我在26例无关的SIOD患者中发现了SMARCAL1基因的隐性突变。SMARCAL1蛋白是一种SNF2蛋白，在单链DNA存在的情况下具有ATPase活性，但其功能尚未确定。这项建议的目标是识别与SMARCAL1相互作用的蛋白质，并定义保守氨基酸的功能；这项研究是My K08的一个很好的辅助工具，它专注于使用果蝇黑腹果蝇遗传学的力量来定义SMARCAL1的运作途径。这种结合遗传学和生物化学的方法来描述SMARCAL1的功能，将增加我们对SMARCAL1的生物学及其对生物体发育的调控的理解，并有助于深入了解该基因突变导致SIOD的机制。

DESCRIPTION (provided by applicant):Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive spondylo-epiphyseal dysplasia characterized by 1) disproportionate short stature with hyperpigmented macules and dysmorphic facial features, 2) proteinuria with progressive renal failure and 3) lymphopenia with defective cellular immunity. In addition, patients with SIOD have a high incidence of thyroid dysfunction, bone marrow hypoplasia, ocular abnormalities, and cerebral ischemia. The progressive renal failure, immunodeficiency, bone marrow hypoplasia and cerebral ischemia cause significant morbidity and mortality. Dialysis and renal transplantation are the only effective treatments for the progressive renal failure and bone marrow transplantation for the blood cytopenia. There are no effective therapies for the growth failure and cerebral ischemia. Nearly all patients die within the first 15 years of life.Over the past 5 years, I have collected DNA samples and clinical information on SIOD patients from 26 families. Using four families in which the parents were consanguineous, I have recently completed a genome-wide screen and mapped SIOD to chromosome 2q34-q35. Subsequently by a candidate gene approach, I have identified recessive mutations in the SMARCAL1 gene in 26 unrelated SIOD patients. The SMARCAL1 protein, which is an SNF2 protein, has ATPase activity in the presence of single stranded DNA, but its function is otherwise undefined. The goal of this proposal is to identify proteins interacting with SMARCAL1 and to define the function of conserved amino acids; this research is an excellent adjunct to my K08 which is focused on using the power of Drosophila melanogaster genetics to define the pathways within which SMARCAL1 operates. This combined genetic and biochemical approach to delineating the function of SMARCAL1 will increase our understanding of the biology of SMARCAL1 and it regulation of organism development as well as provide insight into the mechanism by which mutations in this gene can give rise to SIOD.