Glypican-3-deficient mice exhibit developmental overgrowth and some of theabnormalities typical of Simpson-Golabi-Behmel syndrome

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson -Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal o vergrowth, and a varying range of dysmorphisms. The clinical features of SG BS are very similar to the more extensively studied Beckwith-Wiedemann synd rome (BWS). Since BWS has been associated with biallelic expression of insu lin-like growth factor II (IGF-II), it has been proposed that GPC3 is a neg ative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role. Here, we report that GPC3-deficient mice exhibit several of the clinical fe atures observed in SGBS patients, including developmental overgrowth, perin atal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imp erforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissu e element. The degree of developmental overgrowth of the GPC3-deficient mice is simila r to that of mice deficient in IGF receptor type 2 (IGF2R), a well characte rized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, howeve r, the levels of IGF-II in GPC3 knockouts are similar to those of the norma l littermates.