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The molecular genetic analysis of hemophilia A: a directed search strategy
for the detection of point mutations in the human factor VIII gene
JK Pattinson, DS Millar, JH McVey, CB Grundy, K Wieland, RS Mibashan, U Martinowitz, K Tan-Un, M Vidaud and M Goossens
Haemostasis Research Group, MRC Clinical Research Centre, Harrow, London,
England.
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.
Volume 76,
Issue 11,
pp. 2242-2248,
12/01/1990
Copyright © 1990 by The American Society of Hematology
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