Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2
Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2
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DOI：
10.1182/blood-2005-09-3620
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发表时间：
2006-03-01
期刊：
影响因子：
20.3
通讯作者：
Ginsburg, D
中科院分区：
文献类型：
--
作者：
Zhang, B;McGee, B;Ginsburg, D
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。在这项研究中，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。
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. In this study, 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.