Abstract
Haemophilia A is a common disorder of blood coagulation caused by a deficiency of factor VIII1. It is inherited as an X-linked recessive trait, and one-third of all cases are thought to result from de novo mutations2. The clinical severity of haemophilia A varies markedly among different families and a subset of the patients with severe disease develop antibodies against factor VIII, called inhibitors3. Because of this heterogeneity, it is likely that many different molecular lesions result in haemophilia A. Indeed, of the nine mutations described to date, all appear to be unique changes4–6. However in this study of 83 patients with haemophilia A we have identified two different point mutations, one in exon 18 and one in exon 22, that have recurred independently in unrelated families. Each mutation produces a nonsense codon by a change of CG to TG, and each occurred de novo on the X-chromosome donated by the maternal grandfather. These observations strongly support the view that CpG dinucleotides are mutation hotspots.
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Youssoufian, H., Kazazian, H., Phillips, D. et al. Recurrent mutations in haemophilia A give evidence for CpG mutation hotspots. Nature 324, 380–382 (1986). https://doi.org/10.1038/324380a0
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DOI: https://doi.org/10.1038/324380a0
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