Mutations in the Human Homologue of Drosophila patched in Japanese Nevoid Basal Cell Carcinoma Syndrome Patients
Mutations in the Human Homologue of Drosophila patched in Japanese Nevoid Basal Cell Carcinoma Syndrome Patients
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DOI：
10.1002/humu.9132
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发表时间：
2003-04-01
期刊：
影响因子：
3.9
通讯作者：
Miyashita, Toshiyuki
中科院分区：
文献类型：
--
作者：
Fujii, Katsunori;Kohno, Yoichi;Miyashita, Toshiyuki
人类果蝇补丁同源物(PTCH)的突变已在新生基底细胞癌综合征(NBCCS；也称为Gorlin综合征)以及散发性基底细胞癌和髓母细胞瘤的患者中被发现。然而，使用PCR-SSCP分析，只在一小部分NBCCS患者中发现了PTCH突变(大约三分之一到一半)。在这项研究中，我们确定了PTCH基因的整个基因组组织，并开发了一套新的更准确的引物来分析PTCH基因的突变。使用这些引物，我们对8例日本NBCCS患者的所有PTCH外显子进行了直接测序。结果在6例患者中发现了5个新的PTCH突变，其中1704G>；C和2928G>；C是新发现的。这些突变中的四个，900delC、1247insT、1999delC和933+5G>；T，由于单核苷酸的插入或缺失或异常剪接而导致蛋白质截断。其余突变1514G>；A为错义突变(G509D)。有趣的是，先前已有报道在NBCCS患者中发现了G509V氨基酸替换，这表明该氨基酸残基在PTCH蛋白的功能中发挥着重要作用。以往报道的NBCC中PTCH突变的检出率与我们的不同是由于种族或检测方法的不同。(C)2003年Wiley-Liss，Inc.
Mutations in the human homologue of Drosophila patched (PTCH) have been identified in patients with nevoid basal cell carcinoma syndrome (NBCCS; also called Gorlin syndrome) as well as sporadic basal cell carcinomas and medulloblastomas. However, using PCR-SSCP analysis, mutations in PTCH have been found in only a fraction (about one third to a half) of NBCCS patients. In this study, we determined the whole genomic organizations of the PTCH gene and developed a new set of more accurate primers for the analysis of mutations in PTCH. Using these primers, we examined 8 Japanese NBCCS patients for mutations in all PTCH exons by direct sequencing of the PCR products. As a result, we identified 5 novel PTCH mutations in 6 out of 8 patients including 2 sisters as well as 5 polymorphisms, two of them, 1704G>C and 2928G>C were novel. Four of these mutations, 900delC, 1247insT, 1999delC and 933+5G>T, cause protein truncation due to the insertion or deletion of a single nucleotide or aberrant splicing. The remaining mutation, 1514G>A was a missense alteration (G509D). Interestingly, the amino acid substitution, G509V, has been reported previously in an NBCCS patient, suggesting an important role of this amino acid residue in the function of PTCH protein. The difference in the detection rate of PTCH mutations among NBCCS between previous reports and ours is due to the difference either in ethnicity or in the detection methods. (c) 2003 Wiley-Liss, Inc.