title: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.
abstract: 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.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Jaeger
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Leedham
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Stefania
authors.initials: S
authors.lastname: Segditsas
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Becker
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Pedro Rodenas
authors.initials: PR
authors.lastname: Cuadrado
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Kulvinder
authors.initials: K
authors.lastname: Kaur
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.|Abt. Medizinische Genetik, Universitaetskinderspital beider Basel, Burgfelderstrasse 101, Haus J CH-4055 Basel, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.affiliation: Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: East
authors.affiliation: NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Jenny
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Family Cancer Clinic, Imperial College School of Medicine, St Mark's Hospital, Watford Road, Harrow A1 3UJ, United Kingdom.
authors.forename: Huw
authors.initials: H
authors.lastname: Thomas
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.|NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003111:Colonic Polyps / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D056915:DNA Copy Number Variations; D005326:Fetal Proteins; D000080865:Formins; D020440:Gene Duplication; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins; D051859:Neuroendocrine Secretory Protein 7B2; D009687:Nuclear Proteins; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D013577:Syndrome
chemical_list: D019485:Bone Morphogenetic Proteins; D005326:Fetal Proteins; D000080865:Formins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D051859:Neuroendocrine Secretory Protein 7B2; D009687:Nuclear Proteins; D011971:Receptors, Immunologic; C497678:SCG5 protein, human; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family