Nature Genetics
34, 220 - 225 (2003)
Published online: 28 April 2003; | doi:10.1038/ng1153
Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complexBin Zhang1, Michael A Cunningham2, William C Nichols3, John A Bernat4, Uri Seligsohn5, Steven W Pipe6, John H McVey7, Ursula Schulte-Overberg8, Norma B de Bosch9, Arlette Ruiz-Saez9, Gilbert C. White10, EGD Tuddenham7, Randal J. Kaufman2, 11
& David Ginsburg1, 4, 111
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0650, USA. 2
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109-0650, USA. 3
Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. 4
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0650, USA. 5
The Chaim Sheba Medical Center, Tel-Hashomer and Sackler Faculty of Medicine, Tel Aviv, Israel. 6
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109-0650, USA. 7
MRC Clinical Sciences Center, Imperial College, London W12 ONN, UK. 8
Charite Medical Center, Humboldt University of Berlin, Germany. 9
Centro Nacional de Hemofilia, Banco Municipla de Sangre, Caracas, Venezuela. 10
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA. 11
Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 48109-0650, USA.
Correspondence should be addressed to David Ginsburg ginsburg@umich.eduMutations 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 proteins1. 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 vesicles5, 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 receptors8,
9,
10,
11,
12,
13. 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 F5F8D14,
15. 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.
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