High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome
High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome
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DOI：
10.1002/humu.20253
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发表时间：
2005-12-01
期刊：
影响因子：
3.9
通讯作者：
Friedl, W
中科院分区：
文献类型：
--
作者：
Aretz, S;Stienen, D;Friedl, W
在10-70%的Peutz-Jeghers综合征（PJS）（一种常染色体显性错构瘤性息肉病综合征）患者中发现了STK 11基因的种系突变。第二个位点被假定在一个大比例的PJS患者。迄今为止，STK 11的改变主要包括点突变;只有少数大的缺失已被报道。我们对71例患者的STK 11基因进行了突变分析。其中，56例符合PJS的临床标准，12例仅因粘膜皮肤色素沉着或因孤立的PJS息肉引起的肠道问题而被推定为PJS。其余3例患者的临床信息不可用。通过对STK 11基因编码区的直接测序，我们在71名患者中的37名（52%）中发现了点突变。我们通过多重连接依赖探针扩增（MLPA）方法检查了其余34例患者，并在17例患者中检测到缺失。在4例患者中，缺失延伸到所有10个外显子，在8例患者中，仅缺失启动子区和外显子1。其余缺失包括外显子2-10（2例患者）、外显子2-3、外显子4-5或外显子8。当仅考虑符合PJS临床标准的患者时，总体突变检测率增加到94%（64%点突变和30%大缺失）。在12例推定病例中均未发现突变。总之，我们发现，约三分之一的患者符合临床PJS标准表现出大的基因组缺失，MLPA很容易检测到。通过直接测序或MLPA分别筛查点突变和大缺失，将STK 11基因的突变检测率提高到94%。STK 11基因中可能还有其他突变，这些突变不能通过本文所用的方法检测到。因此，是否存在第二个PJS基因座是值得怀疑的。《Mutat》26（6），513-519，2005年。(c)2005年Wiley，利斯公司
Germline mutations in the STK11 gene have been identified in 10-70% of patients with Peutz-Jeghers syndrome (PJS), an autosomal-dominant hamartomatous polyposis syndrome. A second locus was assumed in a large proportion of PJS patients. To date, STK11 alterations comprise mainly point mutations; only a small number of large deletions have been reported. We performed a mutation analysis for the STK11 gene in 71 patients. Of these, 56 met the clinical criteria for PJS and 12 were presumed to have PJS because of mucocutaneous pigmentation only or bowel problems due to isolated PJS polyps. No clinical information was available for the remaining three patients. By direct sequencing of the coding region of the STK11 gene, we identified point mutations in 37 of 71 patients (52%). We examined the remaining 34 patients by means of the multiplex ligation-dependent probe amplification (MLPA) method, and detected deletions in 17 patients. In four patients the deletion extended over all 10 exons, and in eight patients only the promoter region and exon 1 were deleted. The remaining deletions encompassed exons 2-10 (in two patients), exons 2-3, exons 4-5, or exon 8. When only patients who met the clinical criteria for PJS are considered, the overall mutation detection rate increases to 94% (64% point mutations and 30% large deletions). No mutation was identified in any of the 12 presumed cases. In conclusion, we found that approximately one,third of the patients who met the clinical PJS criteria exhibited large genomic deletions that were readily detectable by MLPA. Screening for point mutations and large deletions by direct sequencing or MLPA, respectively, increased the mutation detection rate in the STK11 gene up to 94%. There may be still other mutations in the STK11 gene that are not detectable by the methods applied here. Therefore, it is questionable whether a second PJS locus exists at all. Hum Mutat 26(6), 513-519, 2005. (c) 2005 Wiley,Liss, Inc.