Analysis of intron 1 factor VIII gene inversion for direct diagnosis in patients with severe haemophilia A in China.

摘要

Haemophilia A (HA) is the most common sex-linked inherited bleeding disorder because of the deficiency of coagulation factor VIII (FVIII). The disease is caused by a wide variety of heterogeneous and infrequent mutations in the FVIII gene. The mutation hot spot of the FVIII gene is the inversion of intron 22 that was observed in 40-50% of severe HA cases, which was identified by Lakich et al. (1993) and Naylor et al. (1993). Brinke et al. (1996) identified a large genomic rearrangement which affects intron 1 of the FVIII gene. Bagnall et al. (2002), demonstrated that this inversion of intron 1 derives from a homologous recombination between two nearly identical 1041-base-pair sequences, intlh-1 and intlh-2, which are oriented in the opposite direction and positioned respectively in intron 1 of the gene and in a more telemetric region, 140 kb outside the gene between the C6.1 and VBP1 genes Bagnall et al. (2002) reported a technique to investigate the inversion, and the prevalence of the inversion was 48% among British patients with severe HA After excluding a frequent intron 22 inversion (Inv22), a screening of the large FVIII gene is necessary The significant prevalence of the intron 1 inversion (Invl) may result in a modification of this strategy whereby the number of cases that require screening of the entire FVIII gene is reduced. Therefore, we evaluated the prevalence of Invl in severe HA patients in China.