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Epigenetic abnormalities of the mannose-6-phosphate/IGF2 receptor gene are uncommon in human overgrowth syndromes
  1. C Gicquel1,
  2. J Weiss2,
  3. J Amiel3,
  4. V Gaston1,
  5. Y Le Bouc1,
  6. C D Scott2
  1. 1Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, INSERM U515, 75012 Paris, France
  2. 2Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales 2065, Australia
  3. 3Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015, Paris, France
  1. Correspondence to:
 Dr C Gicquel
 Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France;

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Overgrowth syndromes (OGS) comprise different disorders with overlapping phenotypes. They demonstrate a variety of features, including pre- and post-natal overgrowth, macroglossia, organomegaly, abdominal wall defects, and hypoglycaemia. They also predispose to the development of embryonic tumours (most commonly Wilms’ tumour).1 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 & Reik2). 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.5,6

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 IGF2.7 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.8–10 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.9,10

IGF2R is developmentally regulated and its expression is maximal during fetal development and organogenesis.11 Its expression pattern correlates with that of the IGF2 and GPC3 genes.12–14 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.15,16 In humans, the imprinting status of IGF2R is controversial. Some data are supportive of a polymorphic imprinting that occurs in the pre-term post-implantation embryo in 25–50% of individuals17–19

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