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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 LMAN1（ERGIC-53）或MCFD2中的突变导致因子V和VIII因子VIII（F5F8D）的组合缺陷。 LMAN1和MCFD2形成了一种蛋白质复合物，可作为货物受体的FRERY FV和FVIII起作用，从内质网向高尔基体。我们分析了先前报道的10个和10个新的F5F8D家庭。 LMAN1或MCFD2基因中的突变占了其中15个家族，其中包括3个等位基因，导致没有LMAN1 mRNA积累。结合我们以前的报告，我们已经确定了LMAN1或MCFD2突变是76个家庭中71个F5F8D的原因。在没有发现突变的5个家族中，有3个是由于误诊，其余2个可能携带LMAN1或MCFD2突变，而直接测序遗漏了MCFD2突变。我们的结果表明，LMAN1和MCFD2中的突变可能解释了所有F5F8D的情况。免疫沉淀和蛋白质印迹分析检测到源自LMAN1（C475R）或MCFD2（I136T）的淋巴细胞中LMAN1-MCFD2复合物的低水平LMAN1-MCFD2复合物，这表明该复合物在FV和FVIII中的临床减少可能并不需要该复合物的完全损失。 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。