title: Analysis of newly detected mutations in the MCFD2 gene giving rise to combined deficiency of coagulation factors V and VIII.
abstract: Combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) (F5F8D) is a rare autosomal recessive disorder characterized by mild-to-moderate bleeding and reduction in FV and FVIII levels in plasma. F5F8D is caused by mutations in one of two different genes, LMAN1 and MCFD2, which encode proteins that form a complex involved in the transport of FV and FVIII from the endoplasmic reticulum to the Golgi apparatus. Here, we report the identification of a novel mutation Asp89Asn in the MCFD2 gene in a Tunisian patient. In the encoded protein, this mutation causes substitution of a negatively charged aspartate, involved in several structurally important interactions, to an uncharged asparagine. To elucidate the structural effect of this mutation, we performed circular dichroism (CD) analysis of secondary structure and stability. In addition, CD analysis was performed on two missense mutations found in previously reported F5F8D patients. Our results show that all analysed mutant variants give rise to destabilized proteins and highlight the importance of a structurally intact and functional MCFD2 for the efficient secretion of coagulation factors V and VIII.
authors.affiliation: Laboratory of Genetics, Immunology and Human Pathologies, Tunis, Tunisia, Sweden. hejer.abdalah@gmail.com
authors.forename: H
authors.initials: H
authors.lastname: Elmahmoudi
authors.forename: E
authors.initials: E
authors.lastname: Wigren
authors.forename: A
authors.initials: A
authors.lastname: Laatiri
authors.forename: A
authors.initials: A
authors.lastname: Jlizi
authors.forename: A
authors.initials: A
authors.lastname: Elgaaied
authors.forename: E
authors.initials: E
authors.lastname: Gouider
authors.forename: Y
authors.initials: Y
authors.lastname: Lindqvist
mesh_terms: D044383:Black People; D002942:Circular Dichroism; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005166:Factor V Deficiency / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006467:Hemophilia A / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D014416:Tunisia; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: C475146:MCFD2 protein, human; D033921:Vesicular Transport Proteins