Alternative titles; symbols
HGNC Approved Gene Symbol: GPC3
Cytogenetic location: Xq26.2 Genomic coordinates (GRCh38) : X:133,535,745-133,985,594 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.2 | Simpson-Golabi-Behmel syndrome, type 1 | 312870 | X-linked recessive | 3 |
| Wilms tumor, somatic | 194070 | 3 |
Members of the glypican family, including GPC3, are heparan sulfate proteoglycans that bind to the exocytoplasmic surface of the plasma membrane through a covalent glycosylphosphatidylinositol (GPI) linkage. The main function of membrane-attached glypicans is to regulate the signaling of WNTs, Hedgehogs, fibroblast growth factors, and bone morphogenetic proteins (Filmus et al., 2008).
To identify the molecular basis for Simpson-Golabi-Behmel syndrome (SGBS; see 312870), also called Simpson dysmorphia syndrome (SDYS), Pilia et al. (1996) adopted a positional cloning approach, using an X/autosome translocation. They used the cell line GM0097, which was deposited in the NIGMS repository in 1974. This cell line originated from a woman diagnosed with Beckwith-Wiedemann syndrome (BWS; 130650) and showed a karyotype with a de novo X;1 translocation. The karyotype suggested that she was affected by the X-linked SGBS rather than BWS, which is determined by a mutation on 11p. They mapped the breakpoint in an existing contig assembled across Xq26 and found a gene, called GPC3 by them, which was interrupted by this translocation. The gene was interrupted in another female patient with overgrowth and an X;16 translocation and exhibited deletions in 3 different SGBS families. The 2,130-bp cDNA encodes a deduced protein of 580 amino acids beginning 151 bp from the start of the sequence. GPC3 shares a number of features with the GPC1 gene (600395).
Filmus et al., 1988 isolated rat Gpc3 as a transcript developmentally regulated in intestine, and Filmus et al., 1995 showed that Gpc3, which they called Oci-5, is GPI-linked heparan sulfate proteoglycan.
Pilia et al. (1996) determined that the GPC3 gene contains 8 exons and encompasses approximately 500 kb.
By fluorescence in situ hybridization, Shen et al. (1997) mapped the GPC3 gene to human Xq26 and rat Xq36.
Using DNA microarrays to compare gene expression patterns in normal human placenta with those in other tissues, Sood et al. (2006) found that several genes involved in growth and tissue remodeling were expressed at relatively higher levels in the villus sections of placenta compared with other tissues. These included GPC3, CDKN1C (600856), and IGF2 (147470). The GPC3 and CDKN1C genes are mutated in patients with Simpson-Golabi-Behmel syndrome and Beckwith-Wiedemann syndrome (130650), respectively, both fetal-placental overgrowth syndromes. In contrast, loss of IGF2 is associated with fetal growth restriction in mice. The relatively higher expression of genes that both promote and suppress growth suggested to Sood et al. (2006) tight and local regulation of the pathways that control placental development.
Capurro et al. (2008) found that GPC3 inhibited soluble hedgehog activity in the medium of SHH (600725)-expressing mouse embryonic fibroblasts and IHH (600726)-expressing human embryonic kidney cells. GPC3 interacted with SHH, but not with the SHH receptor Patched (PTCH1; 601309), and it competed with Patched for SHH binding. Furthermore, GPC3 induced SHH endocytosis and degradation. The heparan sulfate chains of GPC3 were not required for its interaction with SHH, but membrane attachment via the GPI anchor was required.
Maurel et al. (2013) observed that expression of both microRNA-1291 (MIR1291; 615487) and GPC3 was upregulated in hepatocellular carcinoma. They found that MIR1291 did not directly bind to GPC3 mRNA, but rather enhanced its stability by binding to and directing degradation of IRE1A (ERN1; 604033), an endoribonuclease that functions in the endoplasmic reticulum unfolded protein response. In the absence of MIR1291, IRE1A bound a canonical site in the 3-prime UTR of GPC3 and cleaved the mRNA, causing its degradation via the unfolded protein response. Unlike most miRNAs, which typically bind complementary sequences in the 3-prime UTRs of target mRNAs, MIR1291 bound a complementary site in the 5-prime UTR of IRE1A to direct its degradation.
Using a native mouse model of glioblastoma, Yu et al. (2020) discover several driver variants of PIK3CA (171834). They further showed that secreted members of the glypican family are selectively expressed in these tumors, and that GPC3 drives gliomagenesis and hyperexcitability.
In the initial studies of Pilia et al. (1996) in which 6 of the 8 exons of the GPC3 gene were examined, deletions were identified in 3 of 6 patients with SGBS. This suggested that large scale deletions may be responsible for a considerable proportion of cases of Simpson-Golabi-Behmel syndrome. This might not be unexpected given the large region of genomic DNA covered by the GPC3 gene (approximately 500 kb) and the high proportion of deletions found in some other disorders involving large genes, for example, in the dystrophin gene (300377) in patients with Duchenne muscular dystrophy (310200). Lindsay et al. (1997) carried out studies to determine the proportion and type of deletions present in the GPC3 gene in 18 families with SGBS (approximately half of reported cases). Deletions were detected in only 5 families (1 of which had previously been reported). PCR analysis was carried out using primer pairs that amplified fragments from each of the 8 exons of the GPC3 gene and deletions were found in all exons of the gene except exon 3. The results suggested that large scale deletions may be less common in SGBS than was originally thought. One patient, with an exon 4 and 5 deletion, lacked the characteristic facial dysmorphic features. This raised the possibility of involvement of GPC3 gene defects in a wider range of overgrowth disorders.
Simpson-Golabi-Behmel Syndrome, Type 1
Veugelers et al. (2000) identified 1 SGBS patient with a deletion of GPC3 exon 7 (300037.0002). Six SGBS patients showed point mutations in GPC3: 1 frameshift, 3 nonsense, and 1 splice mutation (300037.0004) predicted a loss of function of the glypican-3 protein. One missense mutation, W296R (300037.0003), altered a conserved amino acid found in all glypicans identified to that time. A GPC3 protein that reproduced this mutation was poorly processed and failed to increase the cell surface expression of heparan sulfate, suggesting that this missense mutation is also a loss-of-function mutation.
Sakazume et al. (2007) identified mutations in the GPC3 gene in 7 Japanese boys with SGBS1. One of the boys had an affected younger brother. All the mutations were predicted to result in complete loss of function. Only 1 patient had a large deletion, and there were 5 nonsense and 1 frameshift mutations. There were no apparent genotype/phenotype correlations.
Wilms Tumor, Somatic
White et al. (2002) identified 2 nonconservative single base changes in the GPC3 gene in Wilms tumor (194070) tissue only (300037.0006-300037.0007), implying a possible role of GPC3 in Wilms tumor development. They pointed out that Wilms tumor has been found in a number of patients with Simpson-Golabi-Behmel syndrome (Hughes-Benzie et al., 1996; Xuan et al., 1999).
Capurro et al. (2008) stated that Gpc3-null mouse embryos show significant overgrowth by embryonic day 12.5. They found that embryos between days 10.5 and 13.5 displayed increased hedgehog signaling, as measured by elevated Patched and Gli1 (165220) mRNA levels.
Xuan et al. (1999) demonstrated a 13-bp deletion of nucleotides 391 to 403 in exon 2 of the GPC3 gene in a Dutch Canadian family with Simpson-Golabi-Behmel syndrome type 1 (SGBS1; 312870). This unique mutation was predicted to generate a frameshift with a premature stop codon at nucleotides 445 to 447, resulting in a truncated 79-amino acid protein.
In a patient with Simpson-Golabi-Behmel syndrome type 1 (SGBS1; 312870), Veugelers et al. (2000) reported a deletion of exon 7 of the GPC3 gene. The aberrant GPC3 transcript had an altered reading frame, leading to a premature stop codon in exon 8. Since the predicted protein would lack consensus sites for heparan sulfate attachment and GPI anchorage, the authors concluded that the protein would be nonfunctional.
Veugelers et al. (2000) reported that each of 2 male cousins with Simpson-Golabi-Behmel syndrome type 1 (SGBS1; 312870) harbored a T-to-A transversion at nucleotide 1076 of the GPC3 gene, which resulted in substitution of arginine for tryptophan at position 296 (W296R). This is a residue which is conserved among 5 other mammalian glypicans, and is also found in C. elegans and Drosophila.
In an SGBS1 (312870) fibroblast cell line, Veugelers et al. (2000) found a G-to-T transversion in the GPC3 gene, which is predicted to substitute the splice donor site for exon 5 with an AGT codon, thus adding an aberrant arginine residue to the protein sequence, followed by a premature stop codon. Since GPC3 is not expressed in fibroblasts, the consequences of the mutation could not be confirmed.
In a patient with Simpson-Golabi-Behmel syndrome type 1 (SGBS1; 312870), Veugelers et al. (2000) identified a C-to-T transition at nucleotide 785 in the GPC3 gene, resulting in substitution of a premature stop codon for arginine-199.
White et al. (2002) screened tumor and normal tissue from 41 male cases of Wilms tumor (194070) to determine the presence of sequence variants in the GPC3 gene. Two nonconservative single base changes were present in tumor tissue only, which implied a possible role of GPC3 in Wilms tumor development. One variant was a 558C-T transition in exon 3, changing a basic histidine (his) to an uncharged polar tyrosine (tyr). The other was a 1902G-A transition in exon 8, changing a nonpolar alanine (ala) to a polar threonine (thr) (300037.0007).
White et al. (2002) screened tumor and normal tissue from 41 male cases of Wilms tumor (194070) to determine the presence of sequence variants in the GPC3 gene. Two nonconservative single base changes were present in tumor tissue only, which implied a possible role of GPC3 in Wilms tumor development. One variant was a 558C-T transition in exon 3 (300037.0005), changing a basic histidine (his) to an uncharged polar tyrosine (tyr). The other was a 1902G-A transition in exon 8, changing a nonpolar alanine (ala) to a polar threonine (thr).
Rodriguez-Criado et al. (2005) described a family in which 4 males in 3 different sibships connected through carrier females had SGBS1 (312870) and deletion of exon 6 in the GPC3 gene. In addition to typical features of SGBS, some of them had novel findings, i.e., abnormal sella turcica and 6 lumbar vertebrae in 2 brothers.
In 2 patients from a family with SGBS1 (312870), Rodriguez-Criado et al. (2005) found a splice site mutation (IVS2+1G-A) in the GPC3 gene. The proband had coarse face, broad forehead, deep middle groove on the tongue, preauricular right ear pit, earlobe creases, epicanthus, macroglossia, and narrow palate.
In 2 brothers with SGBS1 (312870), Romanelli et al. (2007) identified a hemizygous 1605C-T transition in exon 4 of the GPC3 gene, resulting in an arg387-to-ter (R387X) substitution. One boy had a severe phenotype with ambiguous genitalia, hydronephrosis, heart defects, and early death. The second boy had classic features of the disorder but survived. The mutation was not identified in the unaffected mother, suggesting germinal mosaicism.
In a 44-year-old man with SGBS1 (312870), Penisson-Besnier et al. (2008) identified a 1666G-A transition in exon 8 of the GPC3 gene, resulting in a gly556-to-arg (G556R) substitution. He developed carotid artery dissection associated with carotid redundancy. Shi and Filmus (2009) generated and transfected the G556R mutation into human 293T cells. The G556R mutation occurs in a region critical for cleavage of GPC3, which is necessary for GPC3 to be anchored to the plasma membrane via GPI linkage. Western blot analysis and immunostaining showed that the mutant G556R protein was not glycanated and was present in the cell lysate and the conditioned medium. The findings indicated that the mutant G556R protein cannot be attached to the GPI anchor, and is therefore released into the conditioned medium once it reaches the cell surface. Further functional studies showed that the G556R mutation resulted in a loss of function.
Capurro, M. I., Xu, P., Shi, W., Li, F., Jia, A., Filmus, J. Glypican-3 inhibits Hedgehog signaling during development by competing with Patched for Hedgehog binding. Dev. Cell 14: 700-711, 2008. [PubMed: 18477453] [Full Text: https://doi.org/10.1016/j.devcel.2008.03.006]
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Maurel, M., Dejeans, N., Taouji, S., Chevet, E., Grosset, C. F. MicroRNA-1291-mediated silencing of IRE1-alpha enhances glypican-3 expression. RNA 19: 778-788, 2013. [PubMed: 23598528] [Full Text: https://doi.org/10.1261/rna.036483.112]
Penisson-Besnier, I., Lebouvier, T., Moizard, M.-P., Ferre, M., Barth, M., Marc, G., Raynaud, M., Bonneau, D. Carotid artery dissection in an adult with the Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. 146A: 464-467, 2008. [PubMed: 18203194] [Full Text: https://doi.org/10.1002/ajmg.a.32154]
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Rodriguez-Criado, G., Magano, L., Segovia, M., Gurrieri, F., Neri, G., Gonzalez-Meneses, A., Gomez de Terreros, I., Valdez, R., Gracia, R., Lapunzina, P. Clinical and molecular studies on two further families with Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. 138A: 272-277, 2005. [PubMed: 16158429] [Full Text: https://doi.org/10.1002/ajmg.a.30920]
Romanelli, V., Arroyo, I., Rodriguez, J. I., Magano, L., Arias, P., Incera, I., Gracia-Bouthelier, R., Lapunzina, P. Germinal mosaicism in Simpson-Golabi-Behmel syndrome. (Letter) Clin. Genet. 72: 384-386, 2007. [PubMed: 17850639] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00871.x]
Sakazume, S., Okamoto, N., Yamamoto, T., Kurosawa, K., Numabe, H., Ohashi, Y., Kako, Y., Nagai, T., Ohashi, H. GPC3 mutations in seven patients with Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. 143A: 1703-1707, 2007. [PubMed: 17603795] [Full Text: https://doi.org/10.1002/ajmg.a.31822]
Shen, T., Sonoda, G., Hamid, J., Li, M., Filmus, J., Buick, R. N., Testa, J. R. Mapping of the Simpson-Golabi-Behmel overgrowth syndrome gene (GPC3) to chromosome X in human and rat by fluorescence in situ hybridization. Mammalian Genome 8: 72 only, 1997. [PubMed: 9021160] [Full Text: https://doi.org/10.1007/s003359900357]
Shi, W., Filmus, J. A patient with the Simpson-Golabi-Behmel syndrome displays a loss-of-function point mutation in GPC3 that inhibits the attachment of this proteoglycan to the cell surface. (Letter) Am. J. Med. Genet. 149A: 552-554, 2009. [PubMed: 19215053] [Full Text: https://doi.org/10.1002/ajmg.a.32669]
Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. Gene expression patterns in human placenta. Proc. Nat. Acad. Sci. 103: 5478-5483, 2006. [PubMed: 16567644] [Full Text: https://doi.org/10.1073/pnas.0508035103]
Veugelers, M., De Cat, B., Muyldermans, S. Y., Reekmans, G., Delande, N., Frints, S., Legius, E., Fryns, J.-P., Schrander-Stumpel, C., Weidle, B., Magdalena, N., David, G. 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. Hum. Molec. Genet. 9: 1321-1328, 2000. [PubMed: 10814714] [Full Text: https://doi.org/10.1093/hmg/9.9.1321]
White, G. R. M., Kelsey, A. M., Varley, J. M., Birch, J. M. Somatic glypican 3 (GPC3) mutations in Wilms' tumour. Brit. J. Cancer 86: 1920-1922, 2002. [PubMed: 12085187] [Full Text: https://doi.org/10.1038/sj.bjc.6600417]
Xuan, J. Y., Hughes-Benzie, R. M., MacKenzie, A. E. A small interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family. J. Med. Genet. 36: 57-58, 1999. [PubMed: 9950367]
Yu, K., Lin, C.-C. J., Hatcher, A., Lozzi, B., Kong, K., Huang-Hobbs, E., Cheng, Y.-T., Beechar, V. B., Zhu, W., Zhang, Y., Chen, F., Mills, G. B., Mohila, C. A., Creighton, C. J., Noebels, J. L., Scott, K. L., Deneen, B. PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. Nature 578: 166-171, 2020. [PubMed: 31996845] [Full Text: https://doi.org/10.1038/s41586-020-1952-2]