Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1
| العنوان: | 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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| المؤلفون: | Jenny C. Taylor, Kimberley Howarth, Kulvinder Kaur, Annabelle Lewis, Huw Thomas, Hayley Davis, Emma Jaeger, Pedro Rodenas Cuadrado, Karl Heinimann, James E. East, Simon J. Leedham, Martin Becker, Ian Tomlinson, Stefania Segditsas |
| المصدر: | Nature genetics Nature Genetics |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | 0303 health sciences, Locus (genetics), Biology, medicine.disease_cause, Bone morphogenetic protein, Molecular biology, Article, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, 030220 oncology & carcinogenesis, Gene expression, Gene duplication, Genetics, medicine, Ectopic expression, Carcinogenesis, Gene, 030304 developmental biology |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1546-1718 1061-4036 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a934cc4709aa6e295e2ae6f405a2e44c http://ora.ox.ac.uk/objects/uuid:da5adec5-c3e9-4a21-8aa1-6d4e4df3f236 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a934cc4709aa6e295e2ae6f405a2e44c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15461718 10614036 |
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