Recurrent mutations and three novel rearrangements in the factor VIII gene
of hemophilia A patients of Italian descent
L Casula, S Murru, M Pecorara, MS Ristaldi, G Restagno, G Mancuso, M Morfini, R De Biasi, F Baudo and A Carbonara
Istituto di Clinica e Biologia dell'Eta Evolutiva, Universita degli Studi
Cagliari, Italy.
Hemophilia A (HA), a common inherited bleeding disorder in humans, is due
to the deficiency or absence of the factor VIII (FVIII) activity. The
cloning of the FVIII gene has made molecular probes available for the
characterization of the basic defect in this disease. In this study we
describe six different mutations in the FVIII gene detected by DNA analysis
of 100 HA patients of Italian descent. In two of them, with a severe
clinical picture, we identified two novel deletions, one in the middle of
the FVIII gene from exons 7 to 22 and the other encompassing the entire
factor VIII gene. Both of these patients produced antibodies to factor
VIII. In a patient with mild HA we detected a duplication of exon 13, which
is a rearrangement not yet described within the FVIII gene. A possible
explanation for the mild phenotype in this patient is that the molecular
defect results in the production of an unstable FVIII protein with residual
10% FVIII activity. Screening by Taq I restriction endonuclease detected
three mutations that were further characterized by direct sequencing on
amplified DNA: a C-T substitution at codon 1960, in exon 18, converting the
codon for arginine to a non- sense codon; and a G-A substitution at codon
2228 and 2326, in exons 24 and 26 respectively, resulting in the
substitution of glutamine for arginine. All three of these mutations have
been previously described. The non-sense mutation and the codon 2228 G-A
mutation was found in patients with severe HA, while the codon 2326 G-A
mutation was associated with a quite severe condition. These results
confirm that the molecular bases of HA are very heterogeneous and provide
further evidence that recurrent mutations are not uncommon in this system.
Volume 75,
Issue 3,
pp. 662-670,
02/01/1990
Copyright © 1990 by The American Society of Hematology
