title: Maternal gametic transmission of translocations or inversions of human chromosome 11p15.5 results in regional DNA hypermethylation and downregulation of CDKN1C expression.
abstract: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with genetic or epigenetic alterations in one of two imprinted domains on chromosome 11p15.5. Rarely, chromosomal translocations or inversions of chromosome 11p15.5 are associated with BWS but the molecular pathophysiology in such cases is not understood. In our series of 3 translocation and 2 inversion patients with BWS, the chromosome 11p15.5 breakpoints map within the centromeric imprinted domain, 2. We hypothesized that either microdeletions/microduplications adjacent to the breakpoints could disrupt genomic sequences important for imprinted gene regulation. An alternate hypothesis was that epigenetic alterations of as yet unknown regulatory DNA sequences, result in the BWS phenotype. A high resolution Nimblegen custom microarray was designed representing all non-repetitive sequences in the telomeric 33 Mb of the short arm of human chromosome 11. For the BWS-associated chromosome 11p15.5 translocations and inversions, we found no evidence of microdeletions/microduplications. DNA methylation was also tested on this microarray using the HpaII tiny fragment enrichment by ligation-mediated PCR (HELP) assay. This high-resolution DNA methylation microarray analysis revealed a gain of DNA methylation in the translocation/inversion patients affecting the p-ter segment of chromosome 11p15, including both imprinted domains. BWS patients that inherited a maternal translocation or inversion also demonstrated reduced expression of the growth suppressing imprinted gene, CDKN1C in Domain 2. In summary, our data demonstrate that translocations and inversions involving imprinted domain 2 on chromosome 11p15.5, alter regional DNA methylation patterns and imprinted gene expression in cis, suggesting that these epigenetic alterations are generated by an alteration in "chromatin context".
authors.affiliation: Dept of Pathology and Laboratory Medicine, BC Cancer Agency - Vancouver Centre, 600 W 10th Ave., Vancouver, BC, Canada V5Z 4E6.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Smith
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Reid
authors.initials: R
authors.lastname: Thompson
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higgins
authors.forename: Idy W
authors.initials: IW
authors.lastname: Chiu
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002503:Centromere; D056905:Chromosome Breakpoints; D007446:Chromosome Inversion; D002880:Chromosomes, Human, Pair 11; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics*; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014178:Translocation, Genetic
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II
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