Genotype-phenotype correlation in combined deficiency of factor V and factor VIII.

Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2.

[1]  A. Bertomoro,et al.  A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. , 2008, Blood.

[2]  H. Hauri,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. , 2008, Blood.

[3]  Chris L. P. Wong,et al.  Combined factors V and VIII deficiency (F5F8D) in a Chinese family due to compound heterozygosity for nonsense mutations of the LMAN1 gene , 2007, British Journal of Haematology.

[4]  Bin Zhang,et al.  Receptor-mediated protein transport in the early secretory pathway. , 2007, Trends in biochemical sciences.

[5]  A. Viswabandya,et al.  Mutations in the MCFD2 gene are predominant among patients with hereditary combined FV and FVIII deficiency (F5F8D) in India , 2007, Haemophilia : the official journal of the World Federation of Hemophilia.

[6]  M. Margaglione,et al.  A new case of combined factor V and factor VIII deficiency further suggests that the LMAN1 M1T mutation is a frequent cause in Italian patients. , 2007, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[7]  D. Bellissimo,et al.  Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. , 2006, Blood.

[8]  H. Hauri,et al.  Cargo Selectivity of the ERGIC‐53/MCFD2 Transport Receptor Complex , 2006, Traffic.

[9]  V. Wiwanitkit.  Spectrum of Bleeding in Acquired Factor V Inhibitor: A Summary of 33 Cases , 2006, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[10]  J. Jesty,et al.  Platelet factor V supports hemostasis in a patient with an acquired factor V inhibitor, as shown by prothrombinase and tenase assays , 2006, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[11]  M. Morris,et al.  Combined factor V – factor VIII deficiency (F5F8D): Compound heterozygosity for two novel truncating mutations in LMAN1 in a consanguineous patient , 2006, Thrombosis and Haemostasis.

[12]  R. Kaufman,et al.  Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. , 2006, Blood.

[13]  Y. Motomura,et al.  Endocytosis and storage of plasma factor V by human megakaryocytes , 2005, Thrombosis and Haemostasis.

[14]  D. Mohanty,et al.  Mutations in the MCFD2 gene and a novel mutation in the LMAN1 gene in Indian families with combined deficiency of factor V and VIII , 2005, American journal of hematology.

[15]  R. Kaufman,et al.  LMAN1 and MCFD2 Form a Cargo Receptor Complex and Interact with Coagulation Factor VIII in the Early Secretory Pathway* , 2005, Journal of Biological Chemistry.

[16]  A. Chuansumrit,et al.  Combined factor V and factor VIII deficiency in a Thai patient: a case report of genotype and phenotype characteristics , 2005, Haemophilia : the official journal of the World Federation of Hemophilia.

[17]  M. Long,et al.  Endocytosis of plasma‐derived factor V by megakaryocytes occurs via a clathrin‐dependent, specific membrane binding event , 2005, Journal of thrombosis and haemostasis : JTH.

[18]  P. Simioni,et al.  Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet‐derived cofactor , 2005, Journal of thrombosis and haemostasis : JTH.

[19]  D. Ginsburg,et al.  Familial multiple coagulation factor deficiencies: new biologic insight from rare genetic bleeding disorders , 2004, Journal of thrombosis and haemostasis : JTH.

[20]  J. Silveira,et al.  Unique in Vivo Modifications of Coagulation Factor V Produce a Physically and Functionally Distinct Platelet-derived Cofactor , 2004, Journal of Biological Chemistry.

[21]  D. Ginsburg,et al.  A mutation in LMAN1 (ERGIC-53) causing combined factor V and factor VIII deficiency is prevalent in Jews originating from the island of Djerba in Tunisia , 2004, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[22]  H. Hauri,et al.  ER export of ERGIC-53 is controlled by cooperation of targeting determinants in all three of its domains , 2003, Journal of Cell Science.

[23]  D. Ginsburg,et al.  Biosynthetic origin and functional significance of murine platelet factor V. , 2003, Blood.

[24]  D. Ginsburg,et al.  The murine platelet and plasma factor V pools are biosynthetically distinct and sufficient for minimal hemostasis. , 2003, Blood.

[25]  R. Kaufman,et al.  Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex , 2003, Nature Genetics.

[26]  B. Dahlbäck,et al.  Anti‐factor V auto‐antibody in the plasma and platelets of a patient with repeated gastrointestinal bleeding , 2003, Journal of thrombosis and haemostasis : JTH.

[27]  M. Olsson,et al.  Polymorphism and recombination events at the ABO locus: a major challenge for genomic ABO blood grouping strategies , 2001, Transfusion medicine.

[28]  T. Kozuka,et al.  Molecular characterization of the ERGIC-53 gene in two Japanese patients with combined factor V–factor VIII deficiency , 2001, Annals of Hematology.

[29]  Shetty,et al.  Combined factor V and VIII deficiency in Indian population , 2000, Haemophilia : the official journal of the World Federation of Hemophilia.

[30]  S. Antonarakis,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Molecular Analysis of the ERGIC-53 Gene in 35 Families With Combined Factor V-Factor VIII Deficiency , 2015 .

[31]  R. Kaufman,et al.  ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families. , 1999, Blood.

[32]  K. Kaushansky,et al.  Secretable human platelet-derived factor V originates from the plasma pool. , 1998, Blood.

[33]  H. Hauri,et al.  Mutations in the ER–Golgi Intermediate Compartment Protein ERGIC-53 Cause Combined Deficiency of Coagulation Factors V and VIII , 1998, Cell.

[34]  H. Hauri,et al.  The Recycling of ERGIC-53 in the Early Secretory Pathway , 1997, The Journal of Biological Chemistry.

[35]  S. Zeinali,et al.  The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103. , 1997, American journal of human genetics.

[36]  A. Bittles,et al.  The comparative role of consanguinity in infant and childhood mortality in Pakistan , 1997, Annals of human genetics.

[37]  J. Kelton,et al.  An autosomal dominant, qualitative platelet disorder associated with multimerin deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen and an epinephrine aggregation defect. , 1996, Blood.

[38]  M. Chester,et al.  A Rapid and Simple ABO Genotype Screening Method Using a Novel B/O2 versus A/O2 Discriminating Nucleotide Substitution at the ABO Locus , 1995, Vox sanguinis.

[39]  P. Mannucci,et al.  Sustained correction of the bleeding time in an afibrinogenaemic patient after infusion of fresh frozen plasma , 1992, British journal of haematology.

[40]  T. L. Cole,et al.  Isolation and study of an acquired inhibitor of human coagulation factor V. , 1986, The Journal of clinical investigation.

[41]  A. Zivelin,et al.  Combined Factor V and Factor VIII Deficiency among Non-Ashkenazi Jews , 1982 .

[42]  K. Mann,et al.  Radioimmunoassay of factor V in human plasma and platelets. , 1982, Blood.

[43]  J. Miletich,et al.  Patients with congenital factor V deficiency have decreased factor Xa binding sites on their platelets. , 1978, The Journal of clinical investigation.