Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency

Combined factor V and factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder. F5F8D is genetically linked to mutations in the transmembrane lectin ERGIC-53 and its soluble interaction partner MCFD2. The ERGIC-53/MCFD2 protein complex functions as transport receptor of coa...

Full description

Saved in:
Bibliographic Details
Published in:Blood Vol. 111; no. 3; p. 1299
Main Authors: Nyfeler, Beat, Kamiya, Yukiko, Boehlen, Françoise, Yamamoto, Kazuo, Kato, Koichi, de Moerloose, Philippe, Hauri, Hans-Peter, Neerman-Arbez, Marguerite
Format: Journal Article
Language:English
Published: United States 01.02.2008
Subjects:
Amino Acid Sequence
Child
Factor V Deficiency - genetics
Factor V Deficiency - metabolism
Female
Gene Deletion
Hemophilia A - genetics
Hemophilia A - metabolism
Humans
Male
Mannose-Binding Lectins - metabolism
Membrane Proteins - metabolism
Molecular Sequence Data
Protein Binding
Vesicular Transport Proteins - chemistry
Vesicular Transport Proteins - genetics
Vesicular Transport Proteins - metabolism
ISSN:0006-4971
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Combined factor V and factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder. F5F8D is genetically linked to mutations in the transmembrane lectin ERGIC-53 and its soluble interaction partner MCFD2. The ERGIC-53/MCFD2 protein complex functions as transport receptor of coagulation factors V and VIII by mediating their export from the endoplasmic reticulum (ER). Here, we studied a F5F8D patient who was found to be a compound heterozygote for 2 novel mutations in MCFD2: a large deletion of 8.4 kb eliminating the 5'UTR of the gene and a nonsense mutation resulting in the deletion of only 3 amino acids (DeltaSLQ) from the C-terminus of MCFD2. Biochemical and structural analysis of the DeltaSLQ mutant demonstrated impaired binding to ERGIC-53 due to modification of the 3-dimensional structure of MCFD2. Our results highlight the importance of the ERGIC-53/MCFD2 protein interaction for the efficient secretion of coagulation factors V and VIII.
Bibliography:ObjectType-Case Study-2
SourceType-Scholarly Journals-1
ObjectType-Feature-4
content type line 23
ObjectType-Report-1
ObjectType-Article-3
ISSN:0006-4971
DOI:10.1182/blood-2007-09-112854