Vidal Francisco, Farssac Elisenda, Tusell Joan, Puig Lluís, Gallardo Dominique
Unitat de Recerca del Centre de Transfusió i Banc de Teixits de Barcelona, Spain.
Thromb Haemost. 2002 Jul;88(1):12-6.
The large number of Alu repeats in the human genome provides abundant opportunities for unequal homologous recombination events that are responsible of several human diseases. We here describe a novel large FVIII gene deletion from a severe hemophilia A patient in which Alu-repetitive elements are directly involved in the origin of the mutation. Using a long-fragment PCR method, a approximately 23 kb deletion was delimited between introns 24 and 25. The resulting FVIII gene had a hybrid 2317-bp intron and lacked exon 25. Absence of exon 25 was confirmed at the RNA level. Multiple sequence alignment of this hybrid intron and normal introns 24 and 25 provided evidence of an homologous recombination event between two Alu repeats and the exact breakpoints were delimited to a 16 bp region. To our knowledge, this is the first report of hemophilia caused by unequal homologous Alu/Alu recombination. This mechanism, commonly related to genetic human disorders, may be involved in a significant number of hemophilia cases considering that FVIII is coded by an Alu-rich gene.
人类基因组中大量的Alu重复序列为导致多种人类疾病的不等位同源重组事件提供了丰富的机会。我们在此描述了一名重度A型血友病患者中一种新的大的FVIII基因缺失，其中Alu重复元件直接参与了突变的起源。使用长片段PCR方法，在第24和25内含子之间界定了一个约23 kb的缺失。产生的FVIII基因有一个2317 bp的杂合内含子，并且缺少第25外显子。在RNA水平证实了第25外显子的缺失。对这个杂合内含子与正常的第24和25内含子进行多序列比对，提供了两个Alu重复序列之间同源重组事件的证据，确切的断点被界定在一个16 bp的区域。据我们所知，这是关于由不等位同源Alu/Alu重组导致血友病的首次报道。考虑到FVIII由一个富含Alu的基因编码，这种通常与人类遗传疾病相关的机制可能在大量血友病病例中起作用。
