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

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked syndrome characterized by pre- and postnatal overgrowth (gigantism), which clinically resembles t he autosomal Beckwith-Wiedemann syndrome (BWS). Deletions and translocation s involving the glypican-3 gene (GPC3) have been shown to be associated wit h SGBS, Occasionally, these deletions also include the glypican-4 gene (GPC 4). Glypicans are heparan sulfate proteoglycans which have a role in the co ntrol of cell growth and cell division. We have examined the mutational sta tus of the GPC3 and GPC4 genes in one patient with Perlman syndrome, three patients with overgrowth without syndrome diagnosis, ten unrelated SGBS-pat ients and 11 BWS patients. We identified one SGBS patient with a deletion o f a GPC3 exon. Six SGBS patients showed point mutations in GPC3. One frames hift, three nonsense, and one splice mutation predict a loss-of-function of the glypican-3 protein. One missense mutation, W296R, changes an amino aci d that is conserved in all glypicans identified so far. A GPC3 protein that reproduces this mutation is poorly processed and fails to increase the cel l surface expression of heparan sulfate, suggesting that this missense muta tion 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-func tion mutations in GPC4 associated with SGBS.