title: Genotype-phenotype correlation in combined deficiency of factor V and factor VIII.
abstract: 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.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, OH 44195, USA. zhangb@ccf.org
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Marta
authors.initials: M
authors.lastname: Spreafico
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zheng
authors.forename: Angela
authors.initials: A
authors.lastname: Yang
authors.forename: Petra
authors.initials: P
authors.lastname: Platzer
authors.forename: Michael U
authors.initials: MU
authors.lastname: Callaghan
authors.forename: Zekai
authors.initials: Z
authors.lastname: Avci
authors.forename: Namik
authors.initials: N
authors.lastname: Ozbek
authors.forename: Johnny
authors.initials: J
authors.lastname: Mahlangu
authors.forename: Tabitha
authors.initials: T
authors.lastname: Haw
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Kandice
authors.initials: K
authors.lastname: Marchant
authors.forename: Edward G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: Uri
authors.initials: U
authors.lastname: Seligsohn
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005165:Factor V / Q000378:metabolism; D005166:Factor V Deficiency / Q000097:blood / Q000235:genetics*; D005169:Factor VIII / Q000378:metabolism; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D005808:Genes, Recessive; D005838:Genotype; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006801:Humans; D008297:Male; D037241:Mannose-Binding Lectins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D033921:Vesicular Transport Proteins / 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; D005165:Factor V; D005169:Factor VIII