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

• Published in: Blood Vol. 111; no. 3; pp. 1299 - 1301
• 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: Washington, DC Elsevier Inc 01.02.2008; The Americain Society of Hematology
• Subjects: Amino Acid Sequence; Biological and medical sciences; Child; Factor V Deficiency - genetics; Factor V Deficiency - metabolism; Female; Gene Deletion; Hematologic and hematopoietic diseases; Hemophilia A - genetics; Hemophilia A - metabolism; Humans; Male; Mannose-Binding Lectins - metabolism; Medical sciences; Membrane Proteins - metabolism; Molecular Sequence Data; Platelet diseases and coagulopathies; Protein Binding; Vesicular Transport Proteins - chemistry; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; C terminal-Sequence; Deletion; Hemopathy; Hematology; Coagulopathy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-09-112854

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 (ΔSLQ) from the C-terminus of MCFD2. Biochemical and structural analysis of the ΔSLQ 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.