Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Nat Genet. 2012 May 6;44(6):699-703. doi: 10.1038/ng.2263.
Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.
遗传性混合息肉综合征（HMPS）的特征是多种结直肠息肉呈明显常染色体显性遗传，受影响个体中结直肠癌的发生率较高。在这里，我们使用遗传图谱、拷贝数分析、高通量测序排除突变、基因表达分析和功能测定表明，HMPS 是由 SCG5 基因 3'端和 GREM1 基因座上游区域的重复引起的。这种不寻常的突变与 GREM1 基因的等位基因特异性表达增加有关。在对照中，GREM1 表达于肠黏膜下肌纤维母细胞，而在 HMPS 个体中，GREM1 主要表达于大肠上皮。HMPS 重复包含预测的增强子元件；其中一些与 GREM1 启动子相互作用，并可在体外驱动基因表达。增加的 GREM1 表达预计会导致骨形态发生蛋白（BMP）通路活性降低，这也是大肠幼年性息肉病发生肿瘤的一种机制。
