Cheadle Jeremy P, Sampson Julian R
Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
DNA Repair (Amst). 2007 Mar 1;6(3):274-9. doi: 10.1016/j.dnarep.2006.11.001. Epub 2006 Dec 11.
Established predisposition genes account for only a small proportion of familial colorectal cancer. Recently, it has been shown that germline mutations in MUTYH predispose to MUTYH-associated polyposis (MAP), an autosomal recessive disorder characterised by multiple colorectal adenomas and carcinomas. MUTYH functions as a base excision repair DNA glycosylase that excises adenines misincorporated opposite 8-oxo-7,8-dihydro-2'-deoxyguanosine, one of the most stable products of oxidative DNA damage. It is the failure to correct this mispair that is thought to give rise to the characteristic signature of G:C-->T:A mutations found in MAP-associated tumours. Here, we review the germline mutation spectrum at the MUTYH locus (comprising 30 truncating and 55 missense/inframe insertion/deletion variants) and the molecular mechanism and biochemical defect(s) underlying this disorder. We also discuss the application of molecular genetic analysis of MUTYH in clinical practice.
已确定的易感基因仅占家族性结直肠癌的一小部分。最近研究表明，MUTYH基因的种系突变易导致MUTYH相关息肉病（MAP），这是一种常染色体隐性疾病，其特征为多发性结直肠腺瘤和癌。MUTYH作为一种碱基切除修复DNA糖基化酶，可切除与8-氧代-7,8-二氢-2'-脱氧鸟苷（氧化DNA损伤最稳定的产物之一）错配掺入的腺嘌呤。正是由于未能纠正这种错配，才被认为导致了MAP相关肿瘤中出现G:C→T:A突变的特征性标记。在此，我们回顾了MUTYH基因座的种系突变谱（包括30个截短突变和55个错义/框内插入/缺失变体）以及该疾病的分子机制和生化缺陷。我们还讨论了MUTYH分子遗传学分析在临床实践中的应用。
