PTCH2 (patched homolog 2 (Drosophila))
2008-02-01 Peter Zaphiropoulos AffiliationDepartment of Biosciences, Nutrition, Karolinska Institute, 14157 Huddinge, Sweden
DNA/RNA
Description
23 exons, approximately 20 kb of genomic sequence. The last exon is exon 22 due to the presence of exons 12A and 12B.
Transcription
Altrenative splice variants, skipping of exons 9 and 10 - maintenance of reading frame, skipping of exon 9 - maintenance of reading frame, skipping of exon 21- change of reading frame. Alternative 3 end - termination within intron 21.
Proteins
Description
Putative 12 transmembrane protein, similar to PTCH1. Receptor of Hedgehog ligands but can not transduce signal activity as PTCH1 does.
Expression
Mainly testis and skin, generally weaker than PTCH1, gene expression dependent on Hedgehog signaling activation, as in PTCH1. However, in PTCH1 the up-regulation of gene expression due to signaling activation results in a negative feedback loop due to inhibition of the activity of the transmenbrane protein, Smoothened, but this does not appear to be the case for PTCH2.
Localisation
Cellular membranes.
Function
Receptor of Hedgehog ligands but lacks the strong capacity of PTCH1 to inhibit the signaling molecule Smoothened, which, through a series of intracellular events, activates the GLI family of transcription factors. Thus, while PTCH1 regulates Smoothened activity depending on Hedgehog ligand binding, PTCH2 is not. This is despite the fact that the three mammalian Hedgehog ligands Sonic, Desert and Indian Hedgehog have similar affinity for both PTCH1 and PTCH2. The expression of the PTCH2 receptor and the Desert Hedgehog ligand in the testis, as well as the requirement of Desert Hedgehog in testicular development has led to the proposal that PTCH2 may mediate the Desert Hedgehog effects in that tissue and could act as a tumor suppressor in germ cell tumors, as these are frequently deleted in 1p33-34. However, no PTCH2 mutations have been identified in such tumors and knock-out mouse models of PTCH2 have not revealed any testicular phenotype.
Homology
Homolog to PTCH1. Mouse, Chicken and Zebrafish have both PTCH homologs but Drosophila only one.
Mutations
Germinal
None described
Somatic
Only two cases reported :
Medulloblastomas, 2bp deletion in exon 8 - germline DNA not checked.
Basal Cell Carcinoma, nucleotide change in intron 20, five bases from 5 splice junction.
Implicated in
Entity name
Various cancers
Note
There are no genetic diseases or tumors where the role of PTCH2 has been clearly demonstrated by the unambiguous detection of PTCH2 mutations that disrupt the protein function.
The various suggestions of a possible role of PTCH2 in tumor development are generally circumstantial and are mostly based on chromosomal deletions that encompass the PTCH2 genomic region. The strongest evidence that PTCH2 hay have a role in tumor development comes from knock-out mouse model systems. Thus while Ptch2(-/-) mice have no obvious phenotype and do not develop tumors, if they are crossed with Ptch1 (+/-) heterozygotes, then the resulting Ptch2(-/-)Ptch1(+/-) mice developed at a higher incidence typical Ptch1(+/-) tumors such as medulloblastomas and rhabdomyosarcomas, suggesting genetic interactions between Ptch2 and Ptch1.
A possible role of PTCH2 in testicular development, acting as a Desert Hedgehog receptor has been suggested.
Overexpression of PTCH2 in basal cell carcinomas cannot compensate for mutated PTCH1 implying distinct roles of the two homologs. This can be rationalized by the very weak capacity of PTCH2 relative to PTCH1 in inhibiting the signaling molecule Smoothened. Additionally, based mostly on chromosomal deletion in the 1p32-34 region where the PTCH2 gene resides, a role in neurofibromas, pituitary tumors, medulloblastomas and meningiomas has been proposed. Also, PTCH2 is implicated in thymus, dental, prostate, ovary, and bone tissue development, as PTCH2 expression has been detected in these tissues.
In a mouse model, deletions of exons 5 to 17 in both Ptch2 alleles did not result in any obvious phenotype. However in the context of Ptch1+/- mice, this deletion of Ptch2 resulted in higher incidence and broader spectrum of tumor formation. In another mouse model of Ptch2, with a targeted insertion in exon 6 that would results in premature termination, the resulting homozygous mice were characterized with alopecia and epidermal hyperplasia.
The various suggestions of a possible role of PTCH2 in tumor development are generally circumstantial and are mostly based on chromosomal deletions that encompass the PTCH2 genomic region. The strongest evidence that PTCH2 hay have a role in tumor development comes from knock-out mouse model systems. Thus while Ptch2(-/-) mice have no obvious phenotype and do not develop tumors, if they are crossed with Ptch1 (+/-) heterozygotes, then the resulting Ptch2(-/-)Ptch1(+/-) mice developed at a higher incidence typical Ptch1(+/-) tumors such as medulloblastomas and rhabdomyosarcomas, suggesting genetic interactions between Ptch2 and Ptch1.
A possible role of PTCH2 in testicular development, acting as a Desert Hedgehog receptor has been suggested.
Overexpression of PTCH2 in basal cell carcinomas cannot compensate for mutated PTCH1 implying distinct roles of the two homologs. This can be rationalized by the very weak capacity of PTCH2 relative to PTCH1 in inhibiting the signaling molecule Smoothened. Additionally, based mostly on chromosomal deletion in the 1p32-34 region where the PTCH2 gene resides, a role in neurofibromas, pituitary tumors, medulloblastomas and meningiomas has been proposed. Also, PTCH2 is implicated in thymus, dental, prostate, ovary, and bone tissue development, as PTCH2 expression has been detected in these tissues.
In a mouse model, deletions of exons 5 to 17 in both Ptch2 alleles did not result in any obvious phenotype. However in the context of Ptch1+/- mice, this deletion of Ptch2 resulted in higher incidence and broader spectrum of tumor formation. In another mouse model of Ptch2, with a targeted insertion in exon 6 that would results in premature termination, the resulting homozygous mice were characterized with alopecia and epidermal hyperplasia.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17436280 | 2007 | Gene expression analysis of the hedgehog signaling cascade in the chick midbrain and spinal cord. | Aglyamova GV et al |
| 16329124 | 2006 | Desert hedgehog-patched 2 expression in peripheral nerves during Wallerian degeneration and regeneration. | Bajestan SN et al |
| 9811851 | 1998 | Characterization of two patched receptors for the vertebrate hedgehog protein family. | Carpenter D et al |
| 12588389 | 2003 | A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1. | Endo H et al |
| 12438747 | 2002 | Genomic structure and refined chromosomal localization of the mouse Ptch2 gene. | Fröhlich L et al |
| 16121254 | 2005 | The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway. | Koudijs MJ et al |
| 11668596 | 2001 | Development of stratum intermedium and its role as a Sonic hedgehog-signaling structure during odontogenesis. | Koyama E et al |
| 15255999 | 2004 | Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR. | Lévy P et al |
| 16849540 | 2006 | Patched2 modulates tumorigenesis in patched1 heterozygous mice. | Lee Y et al |
| 10075838 | 1999 | Characterisation of a second patched gene in the zebrafish Danio rerio and the differential response of patched genes to Hedgehog signalling. | Lewis KE et al |
| 9462734 | 1998 | Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog. | Motoyama J et al |
| 16632755 | 2006 | Sonic hedgehog signaling is important in tooth root development. | Nakatomi M et al |
| 16914743 | 2006 | Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia. | Nieuwenhuis E et al |
| 11784016 | 2001 | Ptc1 and Ptc2 transcripts provide distinct readouts of Hedgehog signaling activity during chick embryogenesis. | Pearse RV 2nd et al |
| 14613484 | 2004 | Distinct roles of PTCH2 splice variants in Hedgehog signalling. | Rahnama F et al |
| 18036996 | 2008 | Transcriptome analysis of differentiating spermatogonia stimulated with kit ligand. | Rossi P et al |
| 17392501 | 2007 | The hedgehog signaling pathway in the mouse ovary. | Russell MC et al |
| 14566027 | 2003 | Expression of hedgehog proteins in the human thymus. | Sacedón R et al |
| 16140195 | 2005 | Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis. | Semevolos SA et al |
| 16707443 | 2006 | Lack of Rb and p53 delays cerebellar development and predisposes to large cell anaplastic medulloblastoma through amplification of N-Myc and Ptch2. | Shakhova O et al |
| 9931336 | 1999 | Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32. | Smyth I et al |
| 14749765 | 2004 | Genomic annotation of the meningioma tumor suppressor locus on chromosome 1p34. | Sulman EP et al |
| 16958114 | 2006 | Expression of hedgehog signalling components in adult mouse testis. | Szczepny A et al |
| 16159933 | 2005 | Expression and function of sonic hedgehog pathway components in pituitary adenomas: evidence for a direct role in hormone secretion and cell proliferation. | Vila G et al |
| 12626524 | 2003 | Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells. | Wang BE et al |
| 15878962 | 2005 | Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. | Wijgerde M et al |
| 11758785 | 2001 | Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice. | Yamago G et al |
| 15581023 | 2004 | Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22. | Zakrzewska M et al |
| 10029063 | 1999 | PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas. | Zaphiropoulos PG et al |
| 17342747 | 2007 | Sonic and desert hedgehog signaling in human fetal prostate development. | Zhu G et al |
Other Information
Locus ID:
NCBI: 8643
MIM: 603673
HGNC: 9586
Ensembl: ENSG00000117425
Variants:
dbSNP: 8643
ClinVar: 8643
TCGA: ENSG00000117425
COSMIC: PTCH2
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000117425 | ENST00000372192 | Q9Y6C5 |
| ENSG00000117425 | ENST00000438067 | H0Y7J2 |
| ENSG00000117425 | ENST00000447098 | Q9Y6C5 |
Expression (GTEx)
Pathways
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38360123 | 2024 | Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts. | 0 |
| 38360123 | 2024 | Identification of rare variants in PTCH2 associated with non-syndromic orofacial clefts. | 0 |
| 34170463 | 2022 | PTCH2 is not a strong candidate gene for gorlin syndrome predisposition. | 10 |
| 34990798 | 2022 | Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers. | 3 |
| 36027694 | 2022 | Reduced PTCH2 expression is associated with glioma development through its regulation of the PTEN/AKT signaling pathway. | 0 |
| 34170463 | 2022 | PTCH2 is not a strong candidate gene for gorlin syndrome predisposition. | 10 |
| 34990798 | 2022 | Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers. | 3 |
| 36027694 | 2022 | Reduced PTCH2 expression is associated with glioma development through its regulation of the PTEN/AKT signaling pathway. | 0 |
| 33047712 | 2020 | [Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1, PTCH2, SHH, SMO genes in Chinese case-parent trios]. | 0 |
| 33047712 | 2020 | [Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1, PTCH2, SHH, SMO genes in Chinese case-parent trios]. | 0 |
| 30021865 | 2019 | Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. | 12 |
| 31233836 | 2019 | PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells. | 7 |
| 30021865 | 2019 | Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms. | 12 |
| 31233836 | 2019 | PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells. | 7 |
| 29109083 | 2018 | Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction. | 9 |
Citation
Peter Zaphiropoulos
PTCH2 (patched homolog 2 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2008-02-01
Online version: http://atlasgeneticsoncology.org/gene/41892
