TY - JOUR
T1 - Mouse mutant embryos overexpressing IGF-II exhibit phenotypic features of he Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes
AU - Eggenschwiler, Jonathan
AU - Ludwig, Thomas
AU - Fisher, Peter
AU - Leighton, Philip A.
AU - Tilghman, Shirley M.
AU - Efstratiadis, Argiris
PY - 1997/12/1
Y1 - 1997/12/1
N2 - 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 chromosome 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.
AB - 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 chromosome 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.
KW - H19
KW - IGF-II
KW - Mouse mutant
KW - Overgrowth syndrome
UR - http://www.scopus.com/inward/record.url?scp=0030660180&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030660180&partnerID=8YFLogxK
U2 - 10.1101/gad.11.23.3128
DO - 10.1101/gad.11.23.3128
M3 - Article
C2 - 9389646
AN - SCOPUS:0030660180
SN - 0890-9369
VL - 11
SP - 3128
EP - 3142
JO - Genes and Development
JF - Genes and Development
IS - 23
ER -