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Blood ; 114(16): 3489-96, 2009 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-19687512

RESUMO

Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease.


Assuntos
Colágeno Tipo II/metabolismo , Colágeno Tipo I/metabolismo , Hemorragia/metabolismo , Mutação de Sentido Incorreto , Multimerização Proteica/genética , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/metabolismo , Substituição de Aminoácidos , Sítios de Ligação/genética , Linhagem Celular , Colágeno Tipo I/genética , Colágeno Tipo II/genética , Família , Feminino , Expressão Gênica , Hemorragia/genética , Humanos , Masculino , Mutagênese Sítio-Dirigida , Ligação Proteica/genética , Estrutura Terciária de Proteína/genética , Proteínas Recombinantes/economia , Proteínas Recombinantes/metabolismo , Doenças de von Willebrand/classificação , Doenças de von Willebrand/genética , Fator de von Willebrand/genética
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