Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene

Abstract

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked syndrome characterized by pre- and postnatal overgrowth (gigantism), which clinically resembles the autosomal Beckwith-Wiedemann syndrome (BWS). Deletions and translocations involving the glypican-3 gene ( GPC3 ) have been shown to be associated with SGBS. Occasionally, these deletions also include the glypican-4 gene ( GPC4 ). Glypicans are heparan sulfate proteoglycans which have a role in the control of cell growth and cell division. We have examined the mutational status of the GPC3 and GPC4 genes in one patient with Perlman syndrome, three patients with overgrowth without syndrome diagnosis, ten unrelated SGBS-patients and 11 BWS patients. We identified one SGBS patient with a deletion of a GPC3 exon. Six SGBS patients showed point mutations in GPC3. One frameshift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein. One missense mutation, W296R, changes an amino acid that is conserved in all glypicans identified so far. A GPC3 protein that reproduces this mutation is poorly processed and fails to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation. In three SGBS patients and in all non-SGBS patients, no mutations could be identified. We found three single nucleotide polymorphisms in the GPC4 gene but no evidence for loss-of-function mutations in GPC4 associated with SGBS.

Glypicans: proteoglycans with a surprise

“…Most of the GPC3 mutations identified so far are point mutations or small deletions encompassing a varying number of exons (31)(32)(33)(34). Given the lack of correlation between patient phenotype and the location of the mutations, it has been proposed that SGBS is caused by the lack of a functional GPC3 protein, with additional genetic factors being responsible for the intra-and interfamilial phenotypic variation (31).…”

“…Not surprisingly, then, the IGF2R-deficient mice display increased levels of IGF-II in blood and tissues (40,41). The GPC3-null mice, on the other hand, have normal levels of IGF-II (33). Furthermore, no direct interaction between IGF-II and GPC3 has been detected (23).…”

Controversies and advances in the management of Wilms' tumour

“…The Simpson Golabi-Behmel syndrome, an X linked overgrowth disorder with phenotypic overlap with BWS, has been shown to involve the GPC 3 gene. 12 However, as yet no mutations in this gene have been found in sporadic Wilms' tumour.…”

Crystal Structure of N-Glycosylated Human Glypican-1 Core Protein

“…4B). A Trp to Arg mutation in GPC3 of the amino acid corresponding to Trp 290 in Gpc1 has been found in a Simpson-Golabi-Behmel syndrome patient, and it results in poor substitution of HS chains to the core protein (44). The mutation would result in a buried positive charge, which would either disrupt or prevent proper folding of GPC3.…”