Epigenetic abnormalities of the mannose-6-phosphate/IGF2 receptor gene are uncommon in human overgrowth syndromes.

O vergrowth syndromes (OGS) comprise different disorders with overlapping phenotypes. They demonstrate a variety of features, including preand postnatal overgrowth, macroglossia, organomegaly, abdominal wall defects, and hypoglycaemia. They also predispose to the development of embryonic tumours (most commonly Wilms’ tumour). The pathogenesis of two different OGS is well established. Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is related to genetic or epigenetic changes in the imprinted 11p15 region resulting in an increased level of IGF2 (reviewed by Maher & Reik). Simpson-Golabi-Behmel syndrome (SGBS; OMIM #312870) is an X linked disease attributed to mutations in the glypican-3 gene (GPC3), which encodes an extracellular proteoglycan believed to interact with insulin-like growth factor II (IGF2) 3 4 and/or other growth factors. 6 The proliferative effects of IGF2 are mediated by the type 1 IGF receptor. In contrast, the mannose-6-phosphate/IGF2 receptor (IGF2R) has an anti-proliferative function, by ensuring the clearance and inactivation of IGF2. This function of IGF2R is well supported by knockout mouse models; mice lacking functional IGF2R (KO-IGF2R) are up to 30% larger than their wild type littermates. The increased growth of KO-IGF2R mice can be attributed to higher IGF2 levels because this phenotype is corrected in KO-IGF2R mice that also lack functional IGF2 or IGF1R. 10 IGF2R is developmentally regulated and its expression is maximal during fetal development and organogenesis. Its expression pattern correlates with that of the IGF2 and GPC3 genes. In the mouse, IGF2R is subject to parental imprinting with a maternal specific expression, and this pattern is maintained throughout development and in all somatic tissues in the adult. 16 In humans, the imprinting status of IGF2R is controversial. Some data are supportive of a polymorphic imprinting that occurs in the pre-term postimplantation embryo in 25–50% of individuals (reviewed by Wutz et al and Wutz & Barlow). However, other data suggest that IGF2R is not imprinted in primates, including humans. Human and mouse IGF2R genes contain two differential methylated regions (DMRs). DMR1 in the IGF2R promoter is differentially methylated only in mice whereas DMR2, in intron 2, is specifically methylated on the maternal allele in both mice and humans. DMR2 acts as a promoter for an antisense RNA that is also imprinted in mice, with expression from the paternal allele. 27 The function of the antisense RNA is not completely understood but the deletion of the paternal DMR2 restores biallelic expression of the sense IGF2R transcript, consistent with an expression competition model. In humans, IGF2R has been implicated as a tumour suppressor gene in various human tumours such as breast 29 and hepatocellular carcinomas and choriocarcinomas. 34 Recently, it has been shown that pre-implantation embryo procedures in sheep may result in an inappropriate epigenetic modification in the imprinted IGF2R gene during early embryogenesis and the demethylation of DMR2, leading to downregulation of the receptor and consequently to OGS.