GPC3 and the Simpson–Golabi–Behmel Syndrome

Abstract

Abstract Most genetically characterized cases of Simpson–Golabi–Behmel syndrome (SGBS) in humans have been linked with mutations in the GPC3 gene located at Xq26 (Pilia et al., 1996), a gene encoding for glypican-3, a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan (Fig. 164–1). However, a severe form of SGBS has also been reported that maps to Xp22 (Brzustowicz et al., 1999), and many patients with the clinical diagnosis of SGBS have as yet no detectable mutations identified within their GPC3 gene. These data suggest that not all cases of SGBS result solely from GPC3 mutations. Six distinct glypican genes have been identified in vertebrates, all encoding heparan sulfate proteoglycans with structural features similar to those shown in Figure 164–1 (Paine-Saunders et al., 1999; Veugelers et al., 1999). Interestingly, the GPC4 gene is located immediately centromeric to GPC3 in both humans (Huber et al., 1998; Veugelers et al., 1998) and mice (Matsuki et al., 1998), and at least one patient with SGBS has been identi2ed with a deletion involving both GPC3 and GPC4 (Veugelers et al., 1998). However, isolated GPC4 mutations have not been identi2ed in any patients with SGBS, and there is no evidence to suggest that patients with mutations involving both GPC3 and GPC4 have any distinct alteration or enhancement of their phenotype. Furthermore, none of the remaining glypican genes have been mapped to loci linked either specifically with SGBS or, more generally, with overgrowth phenotypes in humans, and mutant alleles of other glypican genes in mice do not seem to phenocopy SGBS (S. Saunders, unpublished data). Therefore, cases of SGBS not arising from GPC3 mutations are unlikely to be due to mutations in genes encoding other members of the glypican gene family.