Molecular Diagnostics Laboratory, National Centre of Scientific Research Demokritos, I/RRP, Athens, Greece.
Dis Colon Rectum. 2010 Aug;53(8):1197-201. doi: 10.1007/DCR.0b013e3181dcf0c1.
MUTYH-associated polyposis syndrome is inherited as a recessive trait and is characterized by the presence of colorectal adenomas and cancer predisposition. Carriers of biallelic mutations in the base excision repair gene MUTYH are exposed to an increased risk of colorectal cancer. The aim of this study was to investigate the pathogenicity of the 13-base-pair deletion, c.504 + 19_504 + 31del13, located on intron 6 of the MUTYH gene, which was identified in 2 unrelated Greek patients with MUTYH-associated polyposis.
Genomic DNA and total RNA were extracted from peripheral blood lymphocytes of 2 unrelated families with polyposis. Screening of the entire coding region of the APC gene and MUTYH gene was performed by direct sequencing.
cDNA analysis of a patient homozygous for the c.504 + 19_504 + 31del13 mutation, and a patient heterozygous for the c.504 + 19_504 + 31del13/c.1437_1439delGGA mutations, revealed complete skipping of MUTYH exon 6. A part of the glycosylase catalytic domain, the pseudo-helix-hairpin-helix motif, is located within exon 6, which enhances the pathogenic effect of the mutation.
This study demonstrates a rare pathogenic MUTYH mutation that is possibly associated with a relatively severe MUTYH-associated polyposis phenotype, highlighted by early-onset colorectal cancer. These data can become useful in clinical practice for the appropriate surveillance and management of families with MUTYH-associated polyposis. It is evident that each MUTYH-associated polyposis case should be handled according to its distinct genotype, following a specific prophylaxis protocol to ensure cancer prevention.
MUTYH 相关息肉综合征是一种隐性遗传特征，其特点是存在结直肠腺瘤和癌症易感性。碱基切除修复基因 MUTYH 中双等位基因突变的携带者结直肠癌风险增加。本研究旨在研究位于 MUTYH 基因 6 号内含子上的 13 碱基对缺失 c.504 + 19_504 + 31del13 的致病性，该缺失在 2 例无关的希腊 MUTYH 相关息肉综合征患者中被发现。
从 2 个具有息肉病的无关家庭的外周血淋巴细胞中提取基因组 DNA 和总 RNA。通过直接测序对 APC 基因和 MUTYH 基因的整个编码区进行筛选。
对携带 c.504 + 19_504 + 31del13 突变的纯合子患者和携带 c.504 + 19_504 + 31del13/c.1437_1439delGGA 突变的杂合子患者进行 cDNA 分析，发现 MUTYH 外显子 6 完全缺失。糖苷酶催化结构域的一部分，假螺旋-发夹-螺旋结构基序，位于外显子 6 内，增强了突变的致病效应。
本研究证明了一种罕见的致病性 MUTYH 突变，可能与相对严重的 MUTYH 相关息肉综合征表型相关，其特征是结直肠癌发病较早。这些数据可在临床实践中为 MUTYH 相关息肉综合征患者的适当监测和管理提供依据。显然，每个 MUTYH 相关息肉综合征病例都应根据其独特的基因型进行处理，遵循特定的预防方案以确保癌症预防。
