Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome.
The overgrowth- and tumor-associated Beckwith-Wiedemann syndrome results from dysregulation of imprinted genes on chromosome 11p15.5. Here we show that inherited microdeletions in the H19 differentially methylated region (DMR) that abolish two CTCF target sites cause this disease. Maternal transmission of the deletions results in hypermethylation of the H19 DMR, biallelic IGF2 expression, H19 silencing and Beckwith-Wiedemann syndrome, indicative of loss of function of the IGF2-H19 imprinting control element.
Sparago
Angela
A
Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy.
Cerrato
Flavia
F
Vernucci
Maria
M
Ferrero
Giovanni Battista
GB
Silengo
Margherita Cirillo
MC
Riccio
Andrea
A
D000483:Alleles; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D000076246:CCCTC-Binding Factor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D017353:Gene Deletion; D020868:Gene Silencing; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins / Q000235:genetics
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004268:DNA-Binding Proteins; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II