Context: IGF-II is an imprinted gene (predominantly transcribed from the paternally inherited allele), which has an important role in fetal growth in mice. IGF2 gene expression is regulated by a complex system of enhancers and promoters that determine tissue-specific and development-specific transcription. In mice, enhancers of the IGF2 gene are located up to 260 kb telomeric to the gene. The role of IGF-II in humans is unclear.
Objective: A woman of short adult stature (1.46 m, -3 sd score) born with severe intrauterine growth retardation (1.25 kg at term, -5.4 SD score) and atypical diabetes diagnosed at the age of 23 yr had a balanced chromosomal translocation t(1;11) (p36.22; p15.5). We hypothesized that her phenotype resulted from disruption of her paternally derived IGF2 gene because her daughter who inherited the identical translocation had normal birth weight.
Design: Both chromosomal break points were identified using fluorescent in situ hybridization. Sequence, methylation, and expression of the IGF2 gene was examined. Hyperinsulinemic, euglycemic clamp with glucose tracers and magnetic resonance imaging of the thorax, abdomen, and pelvis were performed.
Results: The 11p15.5 break point mapped 184 kb telomeric of the IGF2 gene. Microsatellite markers confirmed paternal origin of this chromosome. IGF2 gene sequence and methylation was normal. IGF2 gene expression was reduced in lymphoblasts. Clamp studies showed marked hepatic and total insulin resistance. Massive excess sc fat was seen on magnetic resonance imaging despite slim body mass index (21.1 kg/m2).
Conclusions: A break point 184 kb upstream of the paternally derived IGF2 gene, separating it from some telomeric enhancers, resulted in reduced expression in some mesoderm-derived adult tissues causing intrauterine growth retardation, short stature, lactation failure, and insulin resistance with altered fat distribution.