A synonymous mutation in LMAN1 creates an ectopic splice donor site and causes combined deficiency of FV and FVIII.
A synonymous mutation in LMAN1 creates an ectopic splice donor site and causes combined deficiency of FV and FVIII.
复制标题
LMAN1 中的同义突变产生异位剪接供体位点并导致 FV 和 FVIII 联合缺陷。
DOI：
10.1111/jth.12002
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Zhang,B
中科院分区：
文献类型：
--
作者：
Zhu,M;DAS,V;Zheng,C;Majumdar,S;Zhang,B
Combined deficiency of factor V and factor VIII (F5F8D) is manifested by factor V (FV) and factor VIII (FVIII) levels in the 5–30% range [1, 2]. Although the spontaneous bleeding tendency is usually mild to moderate, severe bleeding can occur after trauma or surgery [1, 2]. The molecular basis of this genetic disorder was first determined to be mutations in LMAN1 (lectin, mannose-binding 1, also called ERGIC-53), which encodes a protein residing in the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC)[3]. F5F8D was later demonstrated to be a heterogeneous disorder [4, 5], and the second disease gene was reported in 2003 to be MCFD2 (multiple coagulation factor deficiency gene 2), a small soluble protein with EF hand domains that binds to LMAN1 in the ERGIC [6]. The LMAN1-MCFD2 complex plays a vital role in the cargo trafficking of FV and FVIII from the ER to the Golgi complex [7, 8].At least 33 LMAN1 and 18 MCFD2 mutations have been reported. Most mutations are null mutations resulting from insertion, deletion or splice site mutations. Patients with MCFD2 mutations tend to have lower FV and FVIII levels than patients with LMAN1 mutations, although these two groups of patients are clinically indistinguishable [2]. Only two missense mutations have been reported in LMAN1, both of which destabilize the protein [8, 9]. In contrast, 8 of the 18 reported MCFD2 mutations are missense mutations, all of which are localized to the EF hand domains [1, 2]. Biochemical experiments show that MCFD2 missense mutations abolish LMAN1 binding, indicating the importance of the LMAN1-MCFD2 complex formation for the cargo receptor function [6, 7, 10]. To date all mutations that result in splicing defects in LMAN1 and MCFD2 are located in intronic splice junctions of the genes. We now report a novel mutation in exon 9 of LMAN1 that creates an ectopic splice donor site that displaces the natural splice donor site at the exon 9-intron 9 junction.
