Genomic imprinting defects in the growth disorder Beckwith-Wiedemann syndrome
Citro, Valentina (2009) Genomic imprinting defects in the growth disorder Beckwith-Wiedemann syndrome. [Tesi di dottorato] (Inedito)
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The imprinting control region (IC1) of the human IGF2 and H19 genes is represented by a chromatin insulator located between the two genes that prevents the activation of IGF2 and allows the activation of H19 on the maternal chromosome. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith–Wiedemann syndrome (BWS). These mutations result in the hypermethylation of the remaining IC1 region and loss of IGF2/H19 imprinting. However, other IC1 microdeletions are associated with incompletely penetrant phenotypes and do not affect the methylation of the locus. Our results indicate that the mutant IC1 alleles with abnormally longer cluster of sites for CTCF have reduced affinity for this factor with respect to the alleles with spacing similar to the wild type sequence, suggesting that the organization rather than the number of CTCF sites in the deleted alleles is critical for the gain of methylation and loss of insulator function. Furthermore, a detailed methylation analysis of BWS patients with IC1 hypermethylation and no accompanying deletion showed that the abnormal methylation is mosaic in the majority of the cases and can affect either the entire or only the 3’ half of the regulatory region. In these cases, the epimutation and the phenotype did not cosegregate with the 11p15.5 region. In both the cases with the microdeletions and those without sequence change, the epigenetic abnormalities are usually present in the patients in the mosaic form and probably acquired by post-zygotic de novo methylation.
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