Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency
Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency
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DOI：
10.1007/s00439-009-0742-6
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发表时间：
2010-01-01
期刊：
影响因子：
5.3
通讯作者：
Alhenc-Gelas, Martine
中科院分区：
文献类型：
--
作者：
Picard, Veronique;Chen, Jian-Min;Alhenc-Gelas, Martine
常规用于研究抗凝血酶（AT）缺陷的分子基础的方法不能检测到大的SERPINC 1重排。2000年至2008年，86先证者怀疑有AT遗传性I型缺陷进行了筛选SERPINC 1突变在我们的实验室。通过对63名先证者进行测序分析，确定了与该缺陷有因果关系的突变。我们在这里提出的结果，多重连接依赖探针扩增（MLPA）分析进行了22的23个剩余的先证者，其中测序没有发现突变。在10例患者中检测到杂合状态下的大缺失：5例全基因缺失，5例部分缺失，其中2例缺失外显子6（n = 2），1例缺失外显子1-2（n = 1），2例缺失外显子5-7（n = 2）。外显子6部分缺失是与10-bp插入相关的2，769-bp缺失和1，892-bp缺失，两者都具有位于Alu重复元件内的5'和/或3'断裂点。此外，我们确定了5'断裂点，以前报告的外显子1-2的缺失内的基因外Alu重复。提出了解释这些Alu序列相关缺失的不同突变机制。总的来说，在这个系列中，MLPA检测到的大缺失解释了几乎一半的无法解释的I型AT遗传缺陷病例。
Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.