Montazer Haghighi Mahdi, Radpour Ramin, Aghajani Katayoun, Zali Narges, Molaei Mahsa, Zali Mohammad Reza
Research Center for Gastroenterology and Liver Diseases, Taleghani Hospital, Shaheed Beheshti Medical University, Tehran, Iran.
Int J Colorectal Dis. 2009 Aug;24(8):885-93. doi: 10.1007/s00384-009-0731-1. Epub 2009 May 29.
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found.
The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing.
We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient.
In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.
遗传性非息肉病性结直肠癌（HNPCC）是早发性遗传性结直肠癌最常见的病因。在大多数HNPCC家族中，可发现微卫星不稳定性（MSI）以及DNA错配修复（MMR）基因之一的种系突变。
采用直接测序法分析MMR基因（MLH1、MLH2、MLH6和PMS2）的整个编码序列。此外，还进行了MSI肿瘤检测和免疫组化检测。
我们在三名伊朗HNPCC患者中发现了三个新的MLH1种系突变和一个新的PMS2种系突变。第一个是颠换突变c.346A>C（T116P），发生在MLH1蛋白高度保守的HATPase-c区域。第二个是颠换突变c.736A>T（I246L），导致异亮氨酸变为亮氨酸的氨基酸变化。第三个突变（c.2145,6 delTG）是移码突变，导致下游五个密码子处出现不成熟的终止密码子。这三个突变均在MLH1基因中检测到。另一个突变是转换突变c.676G>A（G207E），在PMS2基因的外显子六中发现，导致甘氨酸变为谷氨酸的氨基酸变化。MSI检测显示，两名患者的微卫星高度不稳定，一名患者的微卫星稳定。
在所有患者中，HNPCC中MMR蛋白的异常表达与上述新突变有关。
