The missense mutation Arg593 --> Cys is related to antibody formation in a patient with mild hemophilia A.

Abstract:

:The development of inhibitory antibodies to factor VIII in patients affected by a mild form of hemophilia A (factor VIII > 0.05 IU/mL) is considered a rare event. In this study, we evaluated the relationship between genotype and anti-factor VIII antibody formation in a patient with mild hemophilia A. Mutation analysis showed that a missense mutation in the factor VIII gene leading to replacement of Arg593 by Cys in the A2 domain of factor VIII was associated with hemophilia A in this patient. The anti-factor VIII antibodies present in the patient's plasma were characterized using metabolically labeled factor VIII fragments expressed in insect cells. The anti-factor VIII antibodies, composed of subclasses IgG2 and IgG4, reacted with both the fragment corresponding to the factor VIII heavy chain and the A2 domain. The Arg593 --> Cys substitution was introduced into the cDNA encoding the A2 domain of factor VIII and the resulting construct was expressed in insect cells. Strikingly, the metabolically labeled A2 domain carrying the Arg593 --> Cys mutation was not recognized by the anti-factor VIII antibodies present in the plasma of the patient. These data indicate that the anti-factor VIII antibodies are exclusively directed against exogenous factor VIII. This strongly suggests that the Arg593 --> Cys substitution results in recognition of wild-type factor VIII as nonself and is thereby related to the formation of anti-factor VIII antibodies after factor VIII replacement therapy in this particular patient.

journal_name

Blood

journal_title

Blood

authors

Fijnvandraat K,Turenhout EA,van den Brink EN,ten Cate JW,van Mourik JA,Peters M,Voorberg J

subject

Has Abstract

pub_date

1997-06-15 00:00:00

pages

4371-7

issue

12

eissn

0006-4971

issn

1528-0020

journal_volume

89

pub_type

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