Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre- and postnatal overgrowth with visceral and skeletal anomalies. To identify the causative gene, breakpoints in two female patients with X;autosome translocations were identified. 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. GPC3 encodes a putative extracellular proteoglycan, glypican 3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action.
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PMID:Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. 858 7

The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth/multiple congenital anomalies/dysplasia syndrome caused by a mutant X-linked gene. The spectrum of its clinical manifestations is broad, varying from very mild forms in carrier females to infantile lethal forms in affected males. A typically affected male will show tall stature, "coarse" face, supernumerary nipples, congenital heart defect, and generalized muscular hypotonia. Mental development is normal in most cases. There is an increased risk of neoplasia in infancy, especially Wilms tumor. The SGBS gene spans 500 kilobases in the Xq26 region and contains eight exons. It encodes an extracellular proteoglycan, designated glypican 3 (GPC3), capable of interacting with the insulin-like growth factor IGF2. At present, only deletions of various sizes have been found in a number of affected families.
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PMID:Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome. 1124 82

Recently, we have shown that mutations in the X-linked glypican 3 (GPC3) gene cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS; ). The next centromeric gene detected is another glypican, glypican 4 (GPC4), with its 5' end 120763bp downstream of the 3' terminus of GPC3. One recovered GPC4 cDNA with an open reading frame of 1668nt encodes a putative protein containing three heparan sulfate glycosylation signals and the 14 signature cysteines of the glypican family. This protein is 94.3% identical to mouse GPC4 and 26% identical to human GPC3. In contrast to GPC3, which produces a single transcript of 2.3kb and is stringently restricted in expression to predominantly mesoderm-derived tissues, Northern analyses show that GPC4 produces two transcripts, 3.4 and 4.6kb, which are very widely expressed (though at a much higher level in fetal lung and kidney). Interestingly, of 20 SGBS patients who showed deletions in GPC3, one was also deleted for part of GPC4. Thus, GPC4 is not required for human viability, even in the absence of GPC3. This patient shows a complex phenotype, including the unusual feature of hydrocephalus; but because an uncle with SGBS is less affected, it remains unclear whether the GPC4 deletion itself contributes to the phenotype.
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PMID:Glypican 3 and glypican 4 are juxtaposed in Xq26.1. 993 7

Embryonal tumors, such as neuroblastoma, medulloblastoma and Wilms' tumor, have their peak incidence in the first 4 years of life. These neoplasias exhibit genetic and clinical heterogeneity, but little is known about their molecular pathogenesis. Application of the differential-display PCR approach led to the identification of a gene, glypican 3 (GPC3), that is differentially expressed in cancer cells. Expression of this gene is usually limited to fetal mesodermal tissue, and its inactivation has been found to be responsible for the X-linked Simpson-Golabi-Behmel overgrowth syndrome. Here, we show that GPC3 mRNA is present in several neuroblastomas and all Wilms' tumors tested to date but not in medulloblastoma. GPC3 was not expressed in normal kidney tissues obtained from the corresponding Wilms' tumor patients, suggesting that in these cancer cells expression was not repressed (or was activated). No correlation was found between expression of GPC3 and the known indicator of neuroblastoma prognosis MYCN mRNA. However, all samples that expressed GPC3 also expressed IGF-II, coding for a growth factor important in the survival and growth of many cancer types. Although the biological significance of this relationship remains unclear, our results suggest that GPC3 may be implicated in the development of embryonal tumors through a signaling pathway that appears to involve IGF-II.
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PMID:Expression of glypican 3 (GPC3) in embryonal tumors. 1100 3

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome caused by deletions in glypican 3 (GPC3). SGBS is characterized by pre- and postnatal overgrowth, a characteristic facial appearance, and a spectrum of congenital malformations which overlaps that of other overgrowth syndromes. We performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: SGBS (n = 19), possible SGBS (n = 26), including families in which individuals had previously been diagnosed with other overgrowth syndromes, and Wiedemann-Beckwith syndrome (WBS) (n = 35). Using exon-specific PCR and Southern blot analysis, we identified seven GPC3 deletions. In most cases a clear X-linked family history was not present. In two cases, GPC3 deletions were identified in patients belonging to pedigrees published previously as other overgrowth syndromes: one with a diagnosis of Sotos syndrome and the other Perlman syndrome with nephroblastomatosis. A third patient developed hepatoblastoma, a tumor type not previously described in SGBS. No GPC3 deletions were identified among the WBS patients. 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. Our results validate the clinical specificity of the facial appearance, skeletal/hand anomalies, and supernumerary nipples in patients with GPC3 deletions. Our data also suggest that nephroblastomatosis and hepatoblastoma are included in the phenotypic spectrum of GPC3 deletions and SGBS, underscoring the importance of tumor surveillance in these children.
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PMID:GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome. 1147 10

The type 1 Simpson-Golabi-Behmel overgrowth syndrome (SGBS1) is caused by loss-of-function mutations of the X-linked GPC3 gene encoding glypican-3, a cell-surface heparan sulfate proteoglycan that apparently plays a negative role in growth control by an unknown mechanism. Mice carrying a Gpc3 gene knockout exhibited several phenotypic features that resemble clinical hallmarks of SGBS1, including somatic overgrowth, renal dysplasia, accessory spleens, polydactyly, and placentomegaly. 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. However, results from a detailed comparative analysis of growth patterns in double mutants lacking GPC3 and also IGF2, IGF1, or the type 1 IGF receptor (IGF1R) provided conclusive genetic evidence inconsistent with the hypothesis that GPC3 acts as a growth suppressor by sequestering or downregulating an IGF ligand. Nevertheless, our data are compatible with a model positing that there is downstream convergence of the independent signaling pathways in which either IGFs or (indirectly) GPC3 participate.
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PMID:Overgrowth of a mouse model of the Simpson-Golabi-Behmel syndrome is independent of IGF signaling. 1184 87

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome with associated visceral and skeletal anomalies. Deletions or point mutations involving the glypican-3 (GPC3) gene at Xq26 are associated with a relatively milder form of this disorder (SGBS1). GPC3 encodes a putative extracellular proteoglycan, glypican-3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. It appears to form a complex with insulin-like growth factor-II (IGF-II), and might thereby modulate IGF-II action. We reviewed the clinical findings of all published patients with SGBS1 with GPC3 mutations to confirm the clinical specificity for the SGBS1 phenotype. Moreover, we report on a new patient with a GPC3 deletion and IGF-II evaluation.
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PMID:Genotype/phenotype correlations of males affected by Simpson-Golabi-Behmel syndrome with GPC3 gene mutations: patient report and review of the literature. 1271 62

Glypican-3 (GPC3) encodes a cell-surface heparan-sulfate proteoglycan mutated in type 1 Simpson-Golabi-Behmel syndrome (SGBS1), an X-linked overgrowth syndrome. The phenotype of SGBS1 patients and of GPC3 knockout mice suggests that GPC3 plays a negative role in cell proliferation, and an apoptosis-inducing role in specific tissues. Ectopic expression of GPC3 in some cell lines has supported the idea that GPC3 inhibits cell growth. Here we report that blocking endogenous GPC3 expression with an antisense transcript promotes the growth of Hep G2 and Hep 3B hepatoma cell lines. Moreover, antisense inhibition releases Hep 3B cells from cell cycle arrest. Hence, our data further support the notion that GPC3 is an inhibitor of cell proliferation and demonstrate that it modulates cell cycle progression.
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PMID:Blocking endogenous glypican-3 expression releases Hep 3B cells from G1 arrest. 1287 92

We have previously shown that the glypican 3 (GPC3) gene was expressed in neuroblastoma (NB) and Wilms' tumour (WT), two embryonal tumours. GPC3 is an X-linked gene that has its peak expression during development and that is downregulated in all investigated tissues after birth. GPC3 expression could be involved in the aetiology of embryonal tumours such as NB and WT. Methylation is known to play a role in gene silencing, notably in chromosome X inactivation. Southern blot- and PCR-based methylation assays were used to assess the methylation status of the GPC3 promoter on genomic DNA from both normal and embryonal tumour cells. In normal cells, the promoter was not methylated in males and partially methylated in females. Our results suggest that DNA methylation of the promoter region is not essential for the transcriptional repression of the GPC3 gene and that the methylation observed in females is probably linked to the inactive X chromosome. In tumour samples, methylation abnormalities have been found exclusively in female NB samples (loss of methylation) and mainly in male WT samples (gain of methylation). Overall, methylation did not significantly correlate with the expression status of GPC3. Although promoter methylation is likely to affect the expression status of the gene, our results suggest that the deregulation of GPC3 transcriptional expression seen in NB and WT involves other regulatory levels.
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PMID:Methylation analysis of the glypican 3 gene in embryonal tumours. 1508 93

The Simpson-Golabi-Behmel syndrome (SGBS) (OMIM 312870) is an overgrowth/multiple congenital anomalies syndrome caused by a semi-dominant X-linked gene encoding glypican 3 (GPC3). It shows great clinical variability, ranging from mild forms in carrier females to lethal forms with failure to thrive in males. The most consistent findings in SGBS are pre- and postnatal macrosomia, characteristic facial anomalies and abnormalities affecting the internal organs, skeleton, and on some occasions, mental retardation of variable degree. SGBS is also associated with an increased risk of developing embryonal tumors, mostly Wilms and liver tumors. We describe two molecularly-confirmed families with SGBS. All patients had typical manifestations of SGBS including some female relatives who had minor manifestations of the disorder. Some patients had novel findings such as a deep V-shaped sella turcica and six lumbar vertebrae. Molecular studies in affected patients showed a deletion of exon 6 in family 1 and an intronic mutation in family 2.
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PMID:Clinical and molecular studies on two further families with Simpson-Golabi-Behmel syndrome. 1615 29


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