Title: Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.
Authors: Freschi, Andrea; Hur, Stella K; Valente, Federica Maria; Ideraabdullah, Folami Y; Sparago, Angela; Gentile, Maria Teresa; Oneglia, Andrea; Di Nucci, Diego; Colucci-D'Amato, Luca; Thorvaldsen, Joanne L; Bartolomei, Marisa S; Riccio, Andrea; Cerrato, Flavia
Published In PLoS Genet, (2018 02)
Abstract: Differential DNA methylation defects of H19/IGF2 are associated with congenital growth disorders characterized by opposite clinical pictures. Due to structural differences between human and mouse, the mechanisms by which mutations of the H19/IGF2 Imprinting Control region (IC1) result in these diseases are undefined. To address this issue, we previously generated a mouse line carrying a humanized IC1 (hIC1) and now replaced the wildtype with a mutant IC1 identified in the overgrowth-associated Beckwith-Wiedemann syndrome. The new humanized mouse line shows pre/post-natal overgrowth on maternal transmission and pre/post-natal undergrowth on paternal transmission of the mutation. The mutant hIC1 acquires abnormal methylation during development causing opposite H19/Igf2 imprinting defects on maternal and paternal chromosomes. Differential and possibly mosaic Igf2 expression and imprinting is associated with asymmetric growth of bilateral organs. Furthermore, tissue-specific imprinting defects result in deficient liver- and placenta-derived Igf2 on paternal transmission and excessive Igf2 in peripheral tissues on maternal transmission, providing a possible molecular explanation for imprinting-associated and phenotypically contrasting growth disorders.
PubMed ID: 29470501
MeSH Terms: Animals; Cells, Cultured; Female; Genomic Imprinting/genetics*; Growth Disorders/congenital*; Growth Disorders/genetics*; Humans; Insulin-Like Growth Factor II/genetics; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Mosaicism*; Mouse Embryonic Stem Cells; Mutation; Organ Specificity/genetics; Phenotype; Pregnancy; RNA, Long Noncoding/genetics