title: Monozygotic twins with neurofibromatosis type 1 (NF1) display differences in methylation of NF1 gene promoter elements, 5' untranslated region, exon and intron 1.
abstract: 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.
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Germany. anja.harder@ukmuenster.de
authors.forename: Anja
authors.initials: A
authors.lastname: Harder
authors.forename: Sabrina
authors.initials: S
authors.lastname: Titze
authors.forename: Lena
authors.initials: L
authors.lastname: Herbst
authors.forename: Thomas
authors.initials: T
authors.lastname: Harder
authors.forename: Katrin
authors.initials: K
authors.lastname: Guse
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.forename: Dieter
authors.initials: D
authors.lastname: Kaufmann
authors.forename: Thorsten
authors.initials: T
authors.lastname: Rosenbaum
authors.forename: Victor Felix
authors.initials: VF
authors.lastname: Mautner
authors.forename: Elke
authors.initials: E
authors.lastname: Windt
authors.forename: Ute
authors.initials: U
authors.lastname: Wahlländer-Danek
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Hartmut
authors.initials: H
authors.lastname: Peters
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation; D004200:Diseases in Twins / Q000235:genetics*; D057890:Epigenomics; D005091:Exons / Q000235:genetics; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D007438:Introns / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D020339:Optic Nerve Glioma / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*; D020506:Untranslated Regions / Q000235:genetics*
chemical_list: D025542:Neurofibromin 1; D020506:Untranslated Regions