Open AccessTissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice
Author(s) -
Andrea Freschi,
Stella K. Hur,
Federica Maria Valente,
Folami Y. Ideraabdullah,
Ángela Sparago,
Maria Teresa Gentile,
Andrea Oneglia,
Diego Di Nucci,
Luca Colucci-D’Amato,
Joanne L. Thorvaldsen,
Marisa S. Bartolomei,
Andrea Riccio,
Flavia Cerrato
Publication year - 2018
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1007243
Subject(s) - imprinting (psychology) , biology , genomic imprinting , genetics , beckwith–wiedemann syndrome , dna methylation , mutant , epigenetics , gene , gene expression
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.