Bleeding disorder tied to defect in cellular transport mechanism

May 05, 2003

ANN ARBOR, Mich.---Defects in a cargo receptor that shuttles proteins from one place to another within the cell lie at the root of a rare bleeding disorder, according to a study published in the June issue of the journal Nature Genetics.

An international research team led by David Ginsburg of the University of Michigan's Life Sciences Institute and the Howard Hughes Medical Institute examined the genes of 19 patients from 12 families with a rare bleeding disorder called Combined Deficiency of Factor V and Factor VIII, or F5F8D for short. The group has concluded that the bleeding disorder isn't due to a problem within these two clotting factors themselves; it's a problem of transporting the factors inside the cell.

Rather than addressing this question with a biochemical approach to the transporter proteins, Ginsburg said they used genetic analysis of the diseased families to find the problem. "That's the power of genetics," he said. "We can learn some fundamental things about biology by looking at the genes of these families with a rare disease."

Factor V and Factor VIII are just two of the many proteins that participate in a complex cascade of chemical reactions that lead to blood clotting. Various forms of abnormal bleeding and clotting have been tied to problems in many of these blood factors, but this disorder simultaneously involves two factors.

Earlier work on the disorder had identified a genetic mutation that causes defects in a protein called LMAN1, which apparently prevented a cell from secreting Factor V and Factor VIII. But about 30 percent of the F5F8D patients had normal levels of LMAN1, so this mutation alone couldn't account for all of the disease. The F5F8D patients in this study were all normal for LMAN1.

What the researchers found is that a mutation in a second gene, called MCFD2, can result in the same disease state. (MCFD2 is short for multiple coagulation factor deficiency 2.) The team identified seven distinct mutations in the MCFD2 gene which appeared in nine of the 12 families studied.

The researchers propose that these two proteins, LMAN1 and MCFD2, bind together to form a transporter which is specifically tailored to carry the two blood clotting factors from the cell's endoplasmic reticulum to the Golgi body. A mutation in the gene that makes either of the two proteins will result in a malformed transporter, and thus the inability to secrete Factor V and Factor VIII.

This work on bleeding disorders may also provide a solution for the opposite problem, clotting disorders. A drug that targeted the MCFD2 protein could reduce both Factor V and Factor VIII, lowering the risk of unwanted blood coagulation. Ginsburg said such a drug might be an attractive alternative to the oral anticoagulants, such as coumadin, because it would not affect other clotting factors. Ginsburg's lab is currently pursuing MCFD2 as a therapeutic target, and the U-M technology transfer office has applied for a patent.

There are still three families in the study who have the bleeding disorder, but weren't found to have mutations in either the LMAN1 or MCFD2 genes. "It's possible that we just missed it in the genetic screen, but it's also possible that there is a third gene involved," Ginsburg said.
Ginsburg's co-author on this work and others involving Factor VIII and LMAN1 is Randal Kaufman, a U-M biological chemistry professor and Howard Hughes investigator. U-M research investigator Bin Zhang is the first author on the paper. Ginsburg is the Warner-Lambert/Parke-Davis Professor of Medicine, departments of internal Medicine and Human Genetics, a charter member of the Life Sciences Institute and a Howard Hughes Medical Institute investigator. Co-authors from Tel Aviv, London, Berlin and Caracas, Venezuela participated by sharing F5F8D patients.

This research was supported by the National Institutes of Health, the Howard Hughes Medical Institute, the National Hemophilia Foundation and the Heart and Stroke Foundation of Canada.

"Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex" is available online at Nature Genetics -
Life Sciences Institute -
Howard Hughes Medical Institute -
National Hemophilia Foundation -

University of Michigan

Related Proteins Articles from Brightsurf:

New understanding of how proteins operate
A ground-breaking discovery by Centenary Institute scientists has provided new understanding as to the nature of proteins and how they exist and operate in the human body.

Finding a handle to bag the right proteins
A method that lights up tags attached to selected proteins can help to purify the proteins from a mixed protein pool.

Designing vaccines from artificial proteins
EPFL scientists have developed a new computational approach to create artificial proteins, which showed promising results in vivo as functional vaccines.

New method to monitor Alzheimer's proteins
IBS-CINAP research team has reported a new method to identify the aggregation state of amyloid beta (Aβ) proteins in solution.

Composing new proteins with artificial intelligence
Scientists have long studied how to improve proteins or design new ones.

Hero proteins are here to save other proteins
Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments.

Designer proteins
David Baker, Professor of Biochemistry at the University of Washington to speak at the AAAS 2020 session, 'Synthetic Biology: Digital Design of Living Systems.' Prof.

Gone fishin' -- for proteins
Casting lines into human cells to snag proteins, a team of Montreal researchers has solved a 20-year-old mystery of cell biology.

Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.

Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.

Read More: Proteins News and Proteins Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to