Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.

Nature Genetics
Emma JaegerIan Tomlinson

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.

References

Sep 1, 1994·Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology·J WienbergC Lengauer
Feb 1, 1997·Gastroenterology·S C WhitelawE Solomon
Jun 6, 1998·Science·J R HoweL A Aaltonen
Jan 19, 2005·Cell Cycle·Qiang TianLinheng Li
Sep 21, 2007·Proceedings of the National Academy of Sciences of the United States of America·Cynthia KosinskiXin Chen
Feb 12, 2008·Current Protocols in Molecular Biology·Adriana MieleJob Dekker
Jul 17, 2008·European Journal of Human Genetics : EJHG·Eli PapaemmanuilUNKNOWN CORGI Consortium
Aug 12, 2009·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Judith A Hobert, Charis Eng
Dec 4, 2010·International Journal of Cancer. Journal International Du Cancer·Ramprasath VenkatachalamRoland P Kuiper

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Citations

Dec 27, 2012·Nature Genetics·Peh Yean CheahChoong Leong Tang
Dec 27, 2012·Nature Genetics·Ian TomlinsonHuw Thomas
Nov 9, 2012·Proceedings of the National Academy of Sciences of the United States of America·Thomas MontavonDenis Duboule
Dec 6, 2012·The American Journal of Surgical Pathology·Christophe RostyDaniel D Buchanan
May 8, 2013·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Orsolya Symmons, François Spitz
Apr 25, 2014·Gastroenterology Report·Noam Shussman, Steven D Wexner
Nov 21, 2013·Journal of Medical Genetics·Frederik J HesTom van Wezel
Feb 7, 2014·Human Molecular Genetics·Laura ValleIgnacio Blanco
Nov 15, 2014·Current Colorectal Cancer Reports·Kristen K CiomborRichard M Goldberg
Feb 14, 2016·BMC Genetics·Jessada ThutkawkorapinAnnika Lindblom
Dec 19, 2015·Cytokine & Growth Factor Reviews·Hayley DavisAristidis Moustakas
Dec 21, 2013·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·John M Carethers
Oct 24, 2015·Genes, Chromosomes & Cancer·Anna RohlinMargareta Nordling
Aug 28, 2012·Pharmacology & Therapeutics·Mark A GlaireDaniel L Worthley
Jul 19, 2015·Gut·Ulrike PetersNiha Zubair
Oct 15, 2013·American Journal of Medical Genetics. Part a·Emanuela Lucci-CordiscoMaurizio Genuardi
Apr 6, 2016·Clinical Therapeutics·Meghan L UnderhillMatthew B Yurgelun
Sep 14, 2015·Surgical Oncology Clinics of North America·Kory Jasperson, Randall W Burt
Dec 17, 2014·Colorectal Disease : the Official Journal of the Association of Coloproctology of Great Britain and Ireland·M T RicciL Varesco
May 15, 2015·The Journal of Pathology·Sujata BiswasSimon Leedham
Oct 28, 2014·Histopathology·Marco Novelli
Jan 30, 2015·The British Journal of Surgery·A D Beggs, M P Dilworth
Mar 5, 2015·Animal Genetics·I ReberC Drögemüller
Feb 11, 2014·Seminars in Cell & Developmental Biology·Daniel B Constam
Apr 16, 2015·European Journal of Human Genetics : EJHG·Stéphanie Baert-DesurmontThierry Frebourg
Jan 15, 2015·Nature Reviews. Gastroenterology & Hepatology·Hans F A VasenAntoni Castells
Nov 14, 2014·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Heather HampelUNKNOWN Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committe
Jun 10, 2016·Cellular Oncology (Dordrecht)·M M HahnA Geurts van Kessel
Jul 2, 2016·Seminars in Cell & Developmental Biology·François Spitz
Oct 6, 2016·Genetic Testing and Molecular Biomarkers·Monica MarabelliGuglielmina Nadia Ranzani
Oct 8, 2016·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Laura Valle
Nov 20, 2016·The Journal of Pathology·Mark A GlaireIan Tomlinson

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Methods Mentioned

BETA
PCR
amplicon sequencing
acetylation
immunoprecipitation
biopsies
genotyping
transfection
Assay

Software Mentioned

OGT
Roche gsMapper
QuantiSNP

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