title: Similarity in joint and mucous bleeding syndromes in type 2N von Willebrand disease and severe hemophilia A coexisting with type 1 von Willebrand disease in two Chinese pedigrees.
abstract: In this study, we investigated the molecular basis of two unrelated Chinese patients with hemostatic disorders. The proband of the first family had severe hemophilia A (HA) coexisting with type 1 von Willebrand disease (VWD) and the proband of the second family had type 2N VWD. Both probands had similar phenotypes, which included joint and mucosal bleeding, very low factor VIII (FVIII) activity (FVIII:C), and moderate reductions in VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:Rco), as well as a normal multimeric pattern. One FVIII mutation and three VWF mutations were identified: FVIII p.R446* and VWF heterozygous p.E216K mutations were detected in proband 1 and compound heterozygosity of VWF mutations (p.R816W and c.1911delC) in proband 2. Transient expression studies in HEK293T cells proved that R816W mutation abolished the binding of FVIII to VWF and slightly impaired protein synthesis and secretion; 1911delC mutation mainly impaired VWF protein synthesis and secretion. These results provided insight into the possible pathogenic mechanism of type 2N VWD in Chinese patients carrying these mutations.
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China; Department of Laboratory Medicine, Shanghai 9th Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: zyl720027@163.com.
authors.forename: H H
authors.initials: HH
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China.
authors.forename: Z F
authors.initials: ZF
authors.lastname: Xing
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: wangxuefeng6336@hotmail.com.
authors.forename: X F
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Q L
authors.initials: QL
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China.
authors.forename: X D
authors.initials: XD
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Shanghai, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Wang
mesh_terms: D000328:Adult; D001780:Blood Coagulation Tests; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006395:Hemarthrosis / Q000209:etiology; D006467:Hemophilia A / Q000150:complications* / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D008297:Male; D009092:Mucous Membrane / Q000473:pathology*; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D056725:von Willebrand Disease, Type 1 / Q000150:complications* / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D056728:von Willebrand Disease, Type 2 / Q000150:complications* / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D005169:Factor VIII
keywords: FVIII; HA; Molecular pathogenesis; Type 2N; VWD; VWF