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Cited by 309Cellular transport and secretionHemophilia Treatment and ResearchPlatelet Disorders and Treatments

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex

Zhang, Bin, Cunningham, Michael A, Nichols, William C, Bernat, John A, Seligsohn, Uri, Pipe, Steven W, McVey, John H, Schulte-Overberg, Ursula, de Bosch, Norma B, Ruiz-Saez, Arlette, White, Gilbert C., Tuddenham, EGD, Kaufman, Randal J., Ginsburg, David·2003·Nature Genetics
DOI 10.1038/ng1153
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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.

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  1. Oeri, J., Matter, M., Isenschmid, H., Hauser, F. & Koller, F. Angeborener mangel an faktor V (parahaemophilie) verbunden mit echter haemophilie A bein zwei brudern. Med. Probl. Paediatr. 1, 575–588 (1954).

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Metadata

Authors
Zhang, B., Cunningham, M. A., Nichols, W. C., Bernat, J. A., Seligsohn, U., Pipe, S. W., McVey, J. H., Schulte-Overberg, U., de Bosch, N. B., Ruiz-Saez, A., White, G. C., Tuddenham, E., Kaufman, R. J., & Ginsburg, D.
Affiliations
  • University of Michigan (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Sheba Medical Center (IL)
  • Imperial College London (GB)
  • Humboldt-Universität zu Berlin (DE)
  • University of North Carolina at Chapel Hill (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Ginsburg, David
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2003-04-28
Volume
34
Issue
2
Pages
220-225
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng1153
OpenAlex
W2085006382
Cited by
309
References
29
Citations by year
2026: 3 · 2025: 5 · 2024: 11 · 2023: 6 · 2022: 11 · 2021: 6 · 2020: 12 · 2019: 7 · 2018: 8 · 2017: 4 · 2016: 5 · 2015: 8 · 2014: 19 · 2013: 18 · 2012: 15
FWCI
8.63
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Open Research (University of Surrey) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
LMAN1, MCFD2, ERGIC-53, factor V deficiency, hemophilia A, bleeding disorders, ER-Golgi transport, cargo receptors, ERGIC, COPII vesicles, calcium-dependent protein interaction, autosomal recessive inheritance
MeSH terms
Amino Acid Sequence, Biological Transport, Active, Carrier Proteins, Endoplasmic Reticulum, Factor V Deficiency, Female, Golgi Apparatus, HeLa Cells, Hemophilia A, Hemorrhage, Humans, Male, Membrane Proteins, Molecular Sequence Data, Mutation, Pedigree, Transfection, Sequence Homology, Amino Acid, Vesicular Transport Proteins, Mannose-Binding Lectins

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