Abstract

Hemophilia A is a common disorder of blood coagulation due to deficiency of clotting Factor VIII. The gene for factor VIII has been cloned and characterized and a search has begun to understand the molecular basis of hemophilia A. In this proposal, we will characterize all the molecular defects in about 300 patients with various forms of hemophilia A. Mutation detection includes screening of PCR products (by denaturing gradient gel electrophoresis or single stranded electrophoresis or other methods) and nucleotide sequencing of mutant amplified DNA products. Mutations that change amino acids in important areas of the factor VIII protein will be analyzed for their consequences on the function of this protein. The analysis will involve study of factor VIII in CRM positive plasmas and study of factor VIII after transient expression of mutant cDNAs into mammalian cells. The work proposed will provide a clearer understanding of: 1) nature of mutations and prenatal origin and 2) structure-function relationship in the factor VIII protein.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL038165-06
Application #
3354223
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1987-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Leaf, Alexander; Xiao, Yong Fu; Kang, Jing X et al. (2003) Prevention of sudden cardiac death by n-3 polyunsaturated fatty acids. Pharmacol Ther 98:355-77
Fakharzadeh, S S; Zhang, Y; Sarkar, R et al. (2000) Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin. Blood 95:2799-805
Neerman-Arbez, M; Antonarakis, S E; Honsberger, A et al. (1999) The 11 kb FGA deletion responsible for congenital afibrinogenaemia is mediated by a short direct repeat in the fibrinogen gene cluster. Eur J Hum Genet 7:897-902
Neerman-Arbez, M; Johnson, K M; Morris, M A et al. (1999) Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency. Blood 93:2253-60
Antonarakis, S E (1998) Molecular genetics of coagulation factor VIII gene and haemophilia A. Haemophilia 4 Suppl 2:1-11
Neerman-Arbez, M; Antonarakis, S E; Blouin, J L et al. (1997) The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103. Am J Hum Genet 61:143-50
Young, M; Inaba, H; Hoyer, L W et al. (1997) Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. Am J Hum Genet 60:565-73
Bi, L; Sarkar, R; Naas, T et al. (1996) Further characterization of factor VIII-deficient mice created by gene targeting: RNA and protein studies. Blood 88:3446-50
Antonarakis, S E; Kazazian, H H; Gitschier, J et al. (1995) Molecular etiology of factor VIII deficiency in hemophilia A. Adv Exp Med Biol 386:19-34
Antonarakis, S E (1995) Molecular genetics of coagulation factor VIII gene and hemophilia A. Thromb Haemost 74:322-8

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