Faculty Collaboration Database

Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet 2003 Jun;34(2):220-5

Date

04/30/2003

Pubmed ID

12717434

DOI

10.1038/ng1153

Scopus ID

2-s2.0-0038278822 (requires institutional sign-in at Scopus site)   228 Citations

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 approximately 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.

Author List

Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D

Author

Gilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Biological Transport, Active
Carrier Proteins
Endoplasmic Reticulum
Factor V Deficiency
Female
Golgi Apparatus
HeLa Cells
Hemophilia A
Hemorrhage
Humans
Male
Mannose-Binding Lectins
Membrane Proteins
Molecular Sequence Data
Mutation
Pedigree
Sequence Homology, Amino Acid
Transfection
Vesicular Transport Proteins