Glypican-3–Deficient Mice Exhibit Developmental Overgrowth and Some of the Abnormalities 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 over- growth, and a varying range of dysmorphisms. The clin- ical features of SGBS are very similar to the more ex- tensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative 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 features observed in SGBS pa- tients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also dis- play mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental ab- normality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-defi- cient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal litter- mates.