title: Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency.
abstract: 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.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Nyfeler
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Françoise
authors.initials: F
authors.lastname: Boehlen
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.forename: Philippe
authors.initials: P
authors.lastname: de Moerloose
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hauri
authors.forename: Marguerite
authors.initials: M
authors.lastname: Neerman-Arbez
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D005166:Factor V Deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006467:Hemophilia A / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C084004:LMAN1 protein, human; C475146:MCFD2 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins