Direct sequencing of all GPC3 exons in the remaining 13 SGBS patients without GPC3 deletions did not identify any further mutations, raising the possibility of alternative silencing mechanisms and/or other genes in the pathogenesis of SGBS.
These results demonstrate that neither the GPC3 gene nor other genes on Xq26 are responsible for all cases of SGBS and that a second SGBS locus resides on Xp22.
Loss of function mutations in <i>GPC3</i> lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor.
The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS.
We then characterized the dose-dependent effects of these factors on GHR expression in HEK293 cells and in mature human SGBS (Simpson-Golabi-Behmel syndrome) adipocytes using quantitative reverse transcriptase-PCR and assessed the function of their putative REs by luciferase-reporter assays, site-directed mutagenesis and chromatin immunoprecipitation (ChIP) assays.
In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS.
Furthermore, our finding of a GPC3 normal daughter of an SGBS carrier with skeletal abnormalities and Wilms tumour raises the possibility of a trans effect from the maternal carrier in SGBS kindreds.
Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer.
In Gpc3/DeltaH19 double mutants (lacking GPC3 and also carrying a deletion around the H19 gene region that causes bialellic expression of the closely linked Igf2 gene by imprint relaxation), the Gpc3-null phenotype was exacerbated, while additional SGBS1 features (omphalocele and skeletal defects) were manifested.
Loss of function mutations in the gene encoding the heparan sulfate proteoglycan Glypican-3 (GPC3) causes an X-linked disorder in humans known as Simpson-Golabi-Behmel Syndrome (SGBS).
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 patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development.
This previously unknown link between glypican-3 and BMP4 function provides evidence of a role for glypicans in vertebrate limb patterning and skeletal development and suggests a mechanism for the skeletal defects seen in SGBS.