Emmerich J, Chadeuf G, Alhenc-Gelas M, Gouault-Heilman M, Toulon P, Fiessinger J N, Aiach M
INSERM CJF 91-01, UFR des Sciences Pharmaceutiques et Biologiques, Université Paris V, France.
Thromb Haemost. 1994 Oct;72(4):534-9.
We report three novel mutations accounting for cases of inherited type I antithrombin (AT) deficiency. Using the polymerase chain reaction (PCR) and direct sequencing of the coding sequences of the AT gene, we found one mutation in exon 4 and two in exon 6. A deletion of 105 bp causing an in-frame deletion of 35 amino acids between Tyr 240 and Gly 276 was found in exon 4. In a second kindred, deletion of two adenines in codon 412-413 introduced a frameshift and a stop codon at position 431. The last mutation was an insertion of ACCG in codon 387, generating a frameshift with a stop codon located at the normal position. The finding of a sequence repeat of nine residues located at the 5' and 3' ends of the deleted fragment might explain the 105 bp deletion by slippage and mispairing at the replication fork during DNA synthesis. The second mutation is the fourth described within a region of six amino acids (between Phe 408 and Arg 413), which seems to be a cluster of mutations. In this case, the presence of a double repeat sequence--TTCCT and AACA--flanking this region could be particularly favorable for slipped mispairing. These results confirm that human gene mutations are not random events but are strongly influenced by DNA flanking sequences.
我们报告了三种导致遗传性I型抗凝血酶（AT）缺乏症病例的新突变。通过聚合酶链反应（PCR）和对AT基因编码序列的直接测序，我们在第4外显子中发现了一个突变，在第6外显子中发现了两个突变。在第4外显子中发现了一个105 bp的缺失，导致Tyr 240和Gly 276之间35个氨基酸的框内缺失。在第二个家族中，密码子412 - 413处两个腺嘌呤的缺失导致移码，并在第431位产生一个终止密码子。最后一个突变是密码子387处插入ACCG，产生移码，终止密码子位于正常位置。在缺失片段的5'和3'末端发现九个残基的序列重复，这可能解释了DNA合成过程中复制叉处的滑动和错配导致的105 bp缺失。第二个突变是在六个氨基酸区域（Phe 408和Arg 413之间）内描述的第四个突变，该区域似乎是一个突变簇。在这种情况下，该区域两侧存在双重复序列——TTCCT和AACA——可能特别有利于滑动错配。这些结果证实，人类基因突变不是随机事件，而是受到DNA侧翼序列的强烈影响。
