Characterization of SMARCAL1:its expression/interactors

SMARCAL1 的表征：其表达/相互作用物

• 批准号: 6530328
• 负责人: CORNELIUS F BOERKOEL
• 金额: $ 7.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530328
• 关键词: chimeric proteins; clinical research; functional /structural genomics; gene expression; gene mutation; genetic disorder; human subject; immunopathology; immunoprecipitation; kidney disorder; mass spectrometry; molecular pathology; patient oriented research; protein localization; skeletal disorder; tissue /cell culture; yeast two hybrid system

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.

描述（由申请人提供）：Schimke免疫-骨性发育不良（SIOD）是一种常染色体隐性脊柱-骨骺发育不良，其特征是1)不成比例的身材矮小，伴有色素沉着斑和畸形的面部特征，2)蛋白尿伴进行性肾衰竭，3)淋巴细胞减少伴细胞免疫缺陷。此外，SIOD患者甲状腺功能障碍、骨髓发育不全、眼部异常、脑缺血发生率高。进行性肾衰竭、免疫缺陷、骨髓发育不全和脑缺血引起显著的发病率和死亡率。透析和肾移植是治疗进行性肾衰竭和骨髓移植治疗血细胞减少的唯一有效方法。对于生长衰竭和脑缺血没有有效的治疗方法。几乎所有患者都在15岁以内死亡。在过去的5年中，我收集了26个家庭SIOD患者的DNA样本和临床资料。我最近完成了一个全基因组筛选，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名不相关的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存在时具有atp酶活性，但其功能尚不明确。该提案的目标是鉴定与SMARCAL1相互作用的蛋白质，并确定保守氨基酸的功能；这项研究是我的K08的一个很好的辅助，K08的重点是利用果蝇遗传学的力量来定义SMARCAL1运作的途径。这种结合遗传和生化的方法来描述SMARCAL1的功能，将增加我们对SMARCAL1生物学及其对生物体发育的调节的理解，并为该基因突变引起SIOD的机制提供见解。