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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents



  history
ID: 538734.0, MPI für molekulare Genetik / Research Group Development and Disease
Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5' untranslated region, exon and intron 1.
Authors:Harder, A.; Titze, S.; Herbst, L.; Harder, T.; Guse, K.; Tinschert, S.; Kaufmann, D.; Rosenbaum, T.; Mautner, V. F.; Windt, E.; Wahlländer-Danek, U.; Wimmer, K.; Mundlos, S.; Peters, H.
Language:English
Date of Publication (YYYY-MM-DD):2010-12-01
Title of Journal:Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies.
Journal Abbrev.:Twin Res Hum Genet
Volume:13
Issue / Number:6
Start Page:582
End Page:594
Copyright:© Australian Academic Press 2010 All Rights Reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description:Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by heterozygotic inactivation of the NF1 tumor suppressor gene at 17q11.2. The associated phenotypes are highly variable, and modifying genes have been proposed to explain at least in part the intriguing expressivity. Given that haploinsufficiency of the NF1 gene product neurofibromin is responsible for some of the clinical manifestations, variations in expression of the wildtype NF1 allele might modify the phenotype. We therefore investigated epigenetic molecular modifications that could result in variable expression of the normal NF1 allele. To exclude confounding by DNA sequence variations, we analyzed monozygotic twin pairs with NF1 who presented with several discordant features. We fine-mapped the methylation pattern of a nearly 1 kb NF1 promoter region in lymphocytes of 8 twin pairs. All twin pairs showed significant intra-pair differences in methylation, especially of specific promoter subregions such as 5'UTR, exon 1 and intron 1 (+7 to +622), transcription factor binding sites and promoter elements like NF1HCS. Furthermore, we detected significant intra-pair differences in cytosine methylation for the region from -249 to -234 with regard to discordance for optic glioma with a higher grade of methylation in glioma cases. In conclusion, our findings of epigenetic differences of the NF1 promoter in leukocytes within mono zygotic twin pairs may serve as a proof of principle for other tissues. The results point towards a role of methylation patterns of the normal NF1 allele for expression differences and for modification of the NF1 phenotype.
Free Keywords:neurofibromatosis type 1;
NF1;
promoter;
methylation;
monozygotic twin pairs
Comment of the Author/Creator:Correspondence: Anja Harder, Institute of Neuropathology, University Hospital Münster, Domagkstrasse 19, 48129 Münster, Germany.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Neuropathology, Charité — Universitätsmedizin Berlin, Germany;
2.Institute of Neuropathy, University Hospital Münster, Münster, Germany;
3.Department of Neuropathology, Charité — Universitätsmedizin Berlin, Germany;
4.Institute of Medical Genetics, Charité — Universitätsmedizin Berlin, Germany;
5.Clinic of Obstetrics, Division of Experimental Obstetrics, Charité — Universitätsmedizin Berlin, Germany;
6.Department of Neuropathology, Charité — Universitätsmedizin Berlin, Germany;
7.Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany;
8.Institute of Human Genetics, University of Ulm, Germany;
9.Children's Hospital, Klinikum Lüdenscheid, Lüdenscheid, Germany;
10.Laboratory for Tumor Biology and Developmental Disorders, Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany;
11.Otto Heubner Centre for Child Care, Department of Social Pediatrics, Charité — Universitätsmedizin Berlin, Germany;
13.Private practice, Großhesselohe, Munich, Germany;
14.Department of Medical Genetics, Molecular and Clinical Pharmacology, Clinical Genetics Section, Medical University Innsbruck, Austria;
15.Institute of Medical Genetics, Charité — Universitätsmedizin Berlin, Germany;
16.Institute of Medical Genetics, Charité — Universitätsmedizin Berlin, Germany.
Identifiers:ISSN:1832-4274 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/21142935 [ID No:2]
DOI:10.1375/twin.13.6.582 [ID No:3]
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