Journal article
Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex
Nature genetics, Vol.34(2), pp.220-225
06/2003
DOI: 10.1038/ng1153
PMID: 12717434
Abstract
Mutations in LMAN1 (also called ERGIC-53) result in combined deficiency of factor V and factor VIII (F5F8D), an autosomal recessive bleeding disorder characterized by coordinate reduction of both clotting proteins. LMAN1 is a mannose-binding type 1 transmembrane protein localized to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC; refs. 2,3), suggesting that F5F8D could result from a defect in secretion of factor V and factor VIII (ref. 4). Correctly folded proteins destined for secretion are packaged in the ER into COPII-coated vesicles, which subsequently fuse to form the ERGIC. Secretion of certain abundant proteins suggests a default pathway requiring no export signals (bulk flow; refs. 6,7). An alternative mechanism involves selective packaging of secreted proteins with the help of specific cargo receptors. The latter model would be consistent with mutations in LMAN1 causing a selective block to export of factor V and factor VIII. But ∼30% of individuals with F5F8D have normal levels of LMAN1, suggesting that mutations in another gene may also be associated with F5F8D. Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1. MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1. These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.
Details
- Title: Subtitle
- Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex
- Creators
- Norma B de Bosch - Centro Nacional de Hemofilia, Banco Municipla de SangreGilbert C White - Department of Medicine, University of North CarolinaMichael A Cunningham - Department of Biological Chemistry, University of MichiganJohn A Bernat - Department of Human Genetics, University of MichiganUri Seligsohn - The Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of MedicineEGD Tuddenham - MRC Clinical Sciences Center, Imperial CollegeWilliam C Nichols - Children's Hospital Medical CenterArlette Ruiz-Saez - Centro Nacional de Hemofilia, Banco Municipla de SangreBin Zhang - University of Michigan–Ann ArborSteven W Pipe - Department of Pediatrics, University of MichiganJohn H McVey - MRC Clinical Sciences Center, Imperial CollegeUrsula Schulte-Overberg - Charite Medical Center, Humboldt University of BerlinRandal J Kaufman - Department of Biological Chemistry, University of Michigan Howard Hughes Medical Institute, University of MichiganDavid Ginsburg - University of Michigan–Ann Arbor
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.34(2), pp.220-225
- DOI
- 10.1038/ng1153
- PMID
- 12717434
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Language
- English
- Date published
- 06/2003
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984093229402771
Metrics
19 Record Views