The molecular genetic analysis of hemophilia A

A directed search strategy for the detection of point mutations in the human factor VIII gene

J. K. Pattinson, D. S. Millar, J. H. McVey, C. B. Grundy, K. Wieland, R. S. Mibashan, U. Martinowitz, K. Tan-Un, M. Vidaud, M. Goossens, M. Sampietro, P. M. Mannucci, M. Krawczak, J. Reiss, B. Zoll, D. Whitmore, S. Bowcock, R. Wensley, A. Ajani, V. Mitchell & 9 others C. Rizza, R. Maia, P. Winter, E. E. Mayne, M. Schwartz, P. J. Green, V. V. Kakkar, E. G D Tuddenham, D. N. Cooper

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Abstract

A directed-search strategy for point mutations in the factor VIII gene causing hemophilia A was used to screen eight potentially hypermutable CpG dinucleotides occurring at sites deemed to be of functional importance. Polymerase chain reaction-amplified DNA samples from 793 unrelated individuals with hemophilia A were screened by discriminant oligonucleotide hybridization. Point mutations were identified in 16 patients that were consistent with a model of 5-methylcytosine (5mC) deamination. Four new examples of recurrent mutation were demonstrated at the following codons: 336 (CGA → TGA). 372 (CGC → TGC). 372 (CGC → CAC). and 1689 (CGC → TGC). These are functionally important cleavage sites for either activated protein C or Thrombin. Further novel C → T transitions were identified in the remaining arginine codons screened (-5, 427, 583, 795, and 1696), resulting in the creation of TGA termination codons. Differences in mutation frequency were found both within and between the CpG sites and between ethnic groups. These differences are assumed to be due to differences in the level of cytosine methylation at these sites, although direct evidence for this inference is lacking.

Original languageEnglish
Pages (from-to)2242-2248
Number of pages7
JournalBlood
Volume76
Issue number11
Publication statusPublished - Dec 1 1990

Fingerprint

5-Methylcytosine
Methylation
Terminator Codon
Polymerase chain reaction
Cytosine
Factor VIII
Hemophilia A
Protein C
Point Mutation
Codon
Thrombin
Oligonucleotides
Arginine
Molecular Biology
Genes
Deamination
DNA
Mutation Rate
Ethnic Groups
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Hematology

Cite this

Pattinson, J. K., Millar, D. S., McVey, J. H., Grundy, C. B., Wieland, K., Mibashan, R. S., ... Cooper, D. N. (1990). The molecular genetic analysis of hemophilia A: A directed search strategy for the detection of point mutations in the human factor VIII gene. Blood, 76(11), 2242-2248.

The molecular genetic analysis of hemophilia A : A directed search strategy for the detection of point mutations in the human factor VIII gene. / Pattinson, J. K.; Millar, D. S.; McVey, J. H.; Grundy, C. B.; Wieland, K.; Mibashan, R. S.; Martinowitz, U.; Tan-Un, K.; Vidaud, M.; Goossens, M.; Sampietro, M.; Mannucci, P. M.; Krawczak, M.; Reiss, J.; Zoll, B.; Whitmore, D.; Bowcock, S.; Wensley, R.; Ajani, A.; Mitchell, V.; Rizza, C.; Maia, R.; Winter, P.; Mayne, E. E.; Schwartz, M.; Green, P. J.; Kakkar, V. V.; Tuddenham, E. G D; Cooper, D. N.

In: Blood, Vol. 76, No. 11, 01.12.1990, p. 2242-2248.

Research output: Contribution to journalArticle

Pattinson, JK, Millar, DS, McVey, JH, Grundy, CB, Wieland, K, Mibashan, RS, Martinowitz, U, Tan-Un, K, Vidaud, M, Goossens, M, Sampietro, M, Mannucci, PM, Krawczak, M, Reiss, J, Zoll, B, Whitmore, D, Bowcock, S, Wensley, R, Ajani, A, Mitchell, V, Rizza, C, Maia, R, Winter, P, Mayne, EE, Schwartz, M, Green, PJ, Kakkar, VV, Tuddenham, EGD & Cooper, DN 1990, 'The molecular genetic analysis of hemophilia A: A directed search strategy for the detection of point mutations in the human factor VIII gene', Blood, vol. 76, no. 11, pp. 2242-2248.
Pattinson JK, Millar DS, McVey JH, Grundy CB, Wieland K, Mibashan RS et al. The molecular genetic analysis of hemophilia A: A directed search strategy for the detection of point mutations in the human factor VIII gene. Blood. 1990 Dec 1;76(11):2242-2248.
Pattinson, J. K. ; Millar, D. S. ; McVey, J. H. ; Grundy, C. B. ; Wieland, K. ; Mibashan, R. S. ; Martinowitz, U. ; Tan-Un, K. ; Vidaud, M. ; Goossens, M. ; Sampietro, M. ; Mannucci, P. M. ; Krawczak, M. ; Reiss, J. ; Zoll, B. ; Whitmore, D. ; Bowcock, S. ; Wensley, R. ; Ajani, A. ; Mitchell, V. ; Rizza, C. ; Maia, R. ; Winter, P. ; Mayne, E. E. ; Schwartz, M. ; Green, P. J. ; Kakkar, V. V. ; Tuddenham, E. G D ; Cooper, D. N. / The molecular genetic analysis of hemophilia A : A directed search strategy for the detection of point mutations in the human factor VIII gene. In: Blood. 1990 ; Vol. 76, No. 11. pp. 2242-2248.
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