Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.

PLoS Genetics
Andrea FreschiFlavia Cerrato

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 contrasti...Continue Reading

References

Sep 2, 1998·The International Journal of Biochemistry & Cell Biology·S D O'Dell, I N Day
Apr 4, 2012·Current Protocols in Molecular Biology·Alexandra Weyrich
Jul 2, 2016·Clinical Genetics·L SoellnerT Eggermann

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Methods Mentioned

BETA
PCR
transgenic

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