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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

Authors
Nyfeler, Beat
Kamiya, Yukiko
Yamamoto, Kazuo
Kato, Koichi
Hauri, Hans-Peter
Published in Blood. 2008, vol. 111, no. 3, p. 1299-301
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.
Keywords Amino Acid SequenceChildFactor V Deficiency/genetics/metabolismFemaleGene DeletionHemophilia A/genetics/metabolismHumansMaleMannose-Binding Lectins/metabolismMembrane Proteins/metabolismMolecular Sequence DataProtein BindingVesicular Transport Proteins/chemistry/genetics/metabolism
Identifiers
PMID: 17971482
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Structures
Research groups Anticorps antiphospholipides (12)
Bases moléculaires des anomalies génétiques de l'hémostase (504)
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(ISO format)
NYFELER, Beat et al. Deletion of 3 residues from the C-terminus of MCFD2 affects binding to ERGIC-53 and causes combined factor V and factor VIII deficiency. In: Blood, 2008, vol. 111, n° 3, p. 1299-301. https://archive-ouverte.unige.ch/unige:1807

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Deposited on : 2009-05-28

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