Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.
Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.
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DOI：
10.1038/ng.2263
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发表时间：
2012-05-06
期刊：
影响因子：
30.8
通讯作者：
Tomlinson I
中科院分区：
文献类型：
--
作者：
Jaeger E;Leedham S;Lewis A;Segditsas S;Becker M;Cuadrado PR;Davis H;Kaur K;Heinimann K;Howarth K;HMPS Collaboration;East J;Taylor J;Thomas H;Tomlinson I
大约 50 年前，伦敦圣马克医院的一个德系犹太人大家庭首次描述了遗传性混合性息肉病综合征 (HMPS)。该家族多种类型的结直肠息肉表现出明显的常染色体显性遗传，其中结直肠癌的个体比例很高。在过去的 15 年里，我们将 HMPS 基因定位到染色体 15q13.3，并鉴定了所有已知 HMPS 家族共有的祖先单倍型。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来表明 HMPS 是由跨越 SCG5 基因 3' 端和 GREM1 基因座上游区域的大量重复引起的。该突变对 SCG5 表达没有影响，但与等位基因特异性 GREM1 表达大幅增加相关。虽然 GREM1 在对照组的肠上皮下肌成纤维细胞中表达，但 HMPS 患者主要在大肠上皮中表达 GREM1。 HMPS重复包含预测的转录增强子元件；我们已经证明其中一些与 GREM1 启动子相互作用并且能够在体外驱动基因表达。预计 GREM1 表达增加会导致骨形态发生蛋白通路活性降低，这种机制也是幼年性大肠息肉病肿瘤发生的基础。 HMPS 的致病机制在孟德尔癌症综合征中极为不寻常，并强调异位基因表达是肿瘤发生的机制。
The hereditary mixed polyposis syndrome (HMPS) was first described about 50 years ago in a large Ashkenazi Jewish family from St Mark’s Hospital, London. The family showed apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma in a high proportion of individuals. In the last 15 years, we have mapped the HMPS gene to chromosome 15q13.3 and identified an ancestral haplotype common to all the known HMPS families. Here, we have used 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 large duplication spanning the 3′ end of the SCG5 gene and a region upstream of the GREM1 locus. This mutation has no effect on SCG5 expression, but is associated with greatly increased, allele-specific GREM1 expression. Whilst GREM1 is expressed in intestinal sub-epithelial myofibroblasts in controls, HMPS patients predominantly express GREM1 in the epithelium of the large bowel. The HMPS duplication contains predicted transcriptional enhancer elements; we have shown that some of these interact with the GREM1 promoter and are capable of driving gene expression in vitro. Increased GREM1 expression is predicted to lead to reduced bone morphogenetic protein pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel. The pathogenic mechanism in HMPS is extremely unusual in Mendelian cancer syndromes and highlights ectopic gene expression as a mechanism of tumorigenesis.