Van de Water N, Williams R, Ockelford P, Browett P
Department of Haematology, Auckland Hospital, University of Auckland, New Zealand.
Thromb Haemost. 1998 May;79(5):938-42.
Large deletions within the factor VIII gene account for approximately 5% of the mutations causing haemophilia A. The characterization of such mutations can provide insights into the molecular mechanisms of these and other deletions in man. We have analyzed a 20.7 kb deletion spanning exons 15 to 20 within the factor VIII gene in a patient with severe haemophilia A. Long range PCR was used to investigate the extent of the deletion and to provide a template for sequencing across the deletion breakpoint. A 38-base insertion homologous to the 3' region of a LINE-1 (L1) element was detected at the breakpoint of the deletion. Normal sequence at the 5' breakpoint in intron 14 was homologous to an L1 flanking region and normal sequence at the 3' breakpoint in intron 20 was homologous to an adjacent sequence within the same L1 flanking region. A molecular mechanism for the deletion involving retrotransposition of a readthrough product of an L1 element plus its 3' flanking region is suggested.
凝血因子VIII基因内的大片段缺失约占导致甲型血友病的突变的5%。此类突变的特征分析有助于深入了解人类这些及其他缺失的分子机制。我们分析了一名重度甲型血友病患者凝血因子VIII基因内一个跨越外显子15至20的20.7 kb缺失。采用长距离PCR研究缺失范围，并为跨越缺失断点进行测序提供模板。在缺失断点处检测到一个与LINE-1（L1）元件3'区域同源的38个碱基的插入。内含子14中5'断点处的正常序列与一个L1侧翼区域同源，内含子20中3'断点处的正常序列与同一L1侧翼区域内的相邻序列同源。提出了一种涉及L1元件通读产物及其3'侧翼区域逆转录转座的缺失分子机制。
