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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.

Original publication

DOI

10.1038/ng.2263

Type

Journal article

Journal

Nat Genet

Publication Date

06/2012

Volume

44

Pages

699 - 703

Addresses

Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Keywords

Bone Morphogenetic Proteins, Chromosome Mapping, Chromosomes, Human, Pair 15, Colonic Polyps, Colorectal Neoplasms, DNA Copy Number Variations, Fetal Proteins, Gene Duplication, Gene Expression, Humans, Intercellular Signaling Peptides and Proteins, Microfilament Proteins, Neuroendocrine Secretory Protein 7B2, Nuclear Proteins, Receptors, Immunologic, Syndrome