Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of the Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes

• Published in: Genes & development 1997-12, Vol.11 (23), p.3128-3142
• Main Authors: Eggenschwiler, J, Ludwig, T, Fisher, P, Leighton, P A, Tilghman, S M, Efstratiadis, A
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - etiology; Abnormalities, Multiple - genetics; Abnormalities, Multiple - metabolism; Adrenal Cortex - abnormalities; Adrenal Cortex - embryology; Animals; Beckwith-Wiedemann Syndrome - etiology; Beckwith-Wiedemann Syndrome - genetics; Beckwith-Wiedemann Syndrome - metabolism; Bone and Bones - abnormalities; Bone and Bones - embryology; Cleft Palate - embryology; Crosses, Genetic; Cyclin-Dependent Kinase Inhibitor p57; Disease Models, Animal; Eye Abnormalities - embryology; Female; Fetal Death; Fetus - abnormalities; Gene Expression Regulation, Developmental; Heart Defects, Congenital; Hernia, Umbilical - embryology; Humans; Insulin-Like Growth Factor II - biosynthesis; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - physiology; Male; Mice; Mice, Mutant Strains; Nuclear Proteins - genetics; Phenotype; Receptor, IGF Type 2 - genetics; Receptor, IGF Type 2 - metabolism; Research Paper; Sequence Deletion
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.11.23.3128

In mice, the imprinted Igf2 gene (expressed from the paternal allele), which encodes a growth-promoting factor (IGF-II), is linked closely to the reciprocally imprinted H19 locus on chromosome 7. Also imprinted (expressed from the maternal allele) is the Igf2r gene on chromsome 17 encoding the type 2 IGF receptor that is involved in degradation of excess IGF-II. Double mutant embryos carrying a deletion around the H19 region and also a targeted Igf2r allele, both inherited maternally, have extremely high levels of IGF-II (7- and 11-fold higher than normal in tissues and serum, respectively) as a result of biallelic Igf2 expression (imprint relaxation by deletion of H19-associated sequence) in combination with lack of the IGF2R-mediated IGF-II turnover. This excess of IGF-II causes somatic overgrowth, visceromegaly, placentomegaly, omphalocele, and cardiac and adrenal defects, which are also features of the Beckwith-Wiedemann syndrome (BWS), a genetically complex human disorder associated with chromosomal abnormalities in the 11p15.5 region where the IGF2 gene resides. In addition, the double mutant mouse embryos exhibit skeletal defects and cleft palate, which are manifestations observed frequently in the Simpson-Golabi-Behmel syndrome, another overgrowth disorder overlapping phenotypically, but not genetically, with BWS.