SELECTIVE SECRETION PATHWAY MEDIATED BY LMAN1 AND MCFD2

LMAN1 和 MCFD2 介导的选择性分泌途径

• 批准号: 7602906
• 负责人: David Ginsburg
• 金额: $ 2.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602906
• 关键词: Accounting; Alleles; Complex; Computer Retrieval of Information on Scientific Projects Database; Endoplasmic Reticulum; Factor V Deficiency; Factor VIII; Family; Funding; Genes; Goals; Golgi Apparatus; Grant; Immunoprecipitation; Institution; Mediating; Messenger RNA; Missense Mutation; Mutation; Pathway Analysis; Pathway interactions; Patients; Plasma Proteins; Proteins; Reporting; Research; Research Personnel; Resources; Source; United States National Institutes of Health; Western Blotting; clinically significant; lymphoblast; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in LMAN1 (ERGIC-53) or MCFD2 cause combined deficiency of factor V and factor VIII (F5F8D). LMAN1 and MCFD2 form a protein complex that functions as a cargo receptor ferrying FV and FVIII from the endoplasmic reticulum to the Golgi. We analyzed 10 previously reported and 10 new F5F8D families. Mutations in the LMAN1 or MCFD2 genes accounted for 15 of these families, including 3 alleles resulting in no LMAN1 mRNA accumulation. Combined with our previous reports, we have identified LMAN1 or MCFD2 mutations as the causes of F5F8D in 71 of 76 families. Among the 5 families in which no mutations were identified, 3 were due to misdiagnosis, with the remaining 2 likely carrying LMAN1 or MCFD2 mutations that were missed by direct sequencing. Our results suggest that mutations in LMAN1 and MCFD2 may account for all cases of F5F8D. Immunoprecipitation and Western blot analysis detected a low level of LMAN1-MCFD2 complex in lymphoblasts derived from patients with missense mutations in LMAN1 (C475R) or MCFD2 (I136T), suggesting that complete loss of the complex may not be required for clinically significant reduction in FV and FVIII. The immediate goal of this project is to identify additional proteins that are secreted via this pathway by analysis of plasma protein levels.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构为 研究中心，而研究中心不一定是研究者所在的机构。 LMAN 1（ERGIC-53）或MCFD 2突变导致因子V和因子VIII（F5 F8 D）的联合缺乏。LMAN 1和MCFD 2形成蛋白质复合物，其作为货物受体将FV和FVIII从内质网运送到高尔基体。我们分析了10个先前报道的和10个新的F5 F8 D家族。LMAN 1或MCFD 2基因突变占这些家族中的15个，包括3个等位基因，导致没有LMAN 1 mRNA积累。结合我们以前的报告，我们已经确定LMAN 1或MCFD 2突变是76个家庭中71个F5 F8 D的原因。在未发现突变的5个家族中，3个是由于误诊，其余2个可能携带直接测序遗漏的LMAN 1或MCFD 2突变。我们的研究结果表明，LMAN 1和MCFD 2的突变可能是所有F5 F8 D病例的原因。免疫沉淀和蛋白质印迹分析检测到来自LMAN 1（C475 R）或MCFD 2（I136 T）错义突变患者的淋巴母细胞中低水平的LMAN 1-MCFD 2复合物，表明FV和FVIII的临床显著降低可能不需要完全丧失复合物。 该项目的直接目标是通过分析血浆蛋白水平来鉴定通过该途径分泌的其他蛋白质。