MOUSE MUTANT EMBRYOS OVEREXPRESSING IGF-II EXHIBIT PHENOTYPIC FEATURES OF THE BECKWITH-WIEDEMANN AND SIMPSON-GOLABI-BEHMEL-SYNDROMES

In mice, the imprinted Igf2 gene (expressed from the paternal allele), which encodes a growth-promoting factor (IGF-II), is linked closely t o the reciprocally imprinted H19 locus on chromosome 7. Also imprinted (expressed from the maternal allele) is the Igf2r gene on chromsome 1 7 encoding the type 2 IGF receptor that is involved in degradation of excess IGF-IL. Double mutant embryos carrying a deletion around the H1 9 region and also a targeted Igf2r allele, both inherited maternally, have extremely high levels of IGF-II (7- and 11-fold higher than norma l in tissues and serum, respectively) as a result of biallelic Igf2 ex pression (imprint relaxation by deletion of H19-associated sequence) i n combination with lack of the IGF2R-mediated IGF-II turnover, This ex cess of IGF-II causes somatic overgrowth, visceromegaly, placentomegal y, omphalocele, and cardiac and adrenal defects, which are also featur es of the Beckwith-Wiedemann syndrome (BWS), a genetically complex hum an disorder associated with chromosomal abnormalities in the 11p15.5 r egion where the IGF2 gene resides. In addition, the double mutant mous e embryos exhibit skeletal defects and cleft palate, which are manifes tations observed frequently in the Simpson-Golabi-Behmel syndrome, ano ther overgrowth disorder overlapping phenotypically, but not genetical ly, with BWS.