PTCH2 (patched homolog 2 (Drosophila))

2008-02-01   Peter Zaphiropoulos 

Department of Biosciences, Nutrition, Karolinska Institute, 14157 Huddinge, Sweden

Identity

HGNC
PTCH2
LOCATION
1p34.1
LOCUSID
8643
ALIAS
PTC2
FUSION GENES
Show Gene Fusions

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.

    Bibliography

    Pubmed IDLast YearTitleAuthors
    174362802007Gene expression analysis of the hedgehog signaling cascade in the chick midbrain and spinal cord.Aglyamova GV et al
    163291242006Desert hedgehog-patched 2 expression in peripheral nerves during Wallerian degeneration and regeneration.Bajestan SN et al
    98118511998Characterization of two patched receptors for the vertebrate hedgehog protein family.Carpenter D et al
    125883892003A possible paracrine hedgehog signalling pathway in neurofibromas from patients with neurofibromatosis type 1.Endo H et al
    124387472002Genomic structure and refined chromosomal localization of the mouse Ptch2 gene.Fröhlich L et al
    161212542005The zebrafish mutants dre, uki, and lep encode negative regulators of the hedgehog signaling pathway.Koudijs MJ et al
    116685962001Development of stratum intermedium and its role as a Sonic hedgehog-signaling structure during odontogenesis.Koyama E et al
    152559992004Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR.Lévy P et al
    168495402006Patched2 modulates tumorigenesis in patched1 heterozygous mice.Lee Y et al
    100758381999Characterisation of a second patched gene in the zebrafish Danio rerio and the differential response of patched genes to Hedgehog signalling.Lewis KE et al
    94627341998Ptch2, a second mouse Patched gene is co-expressed with Sonic hedgehog.Motoyama J et al
    166327552006Sonic hedgehog signaling is important in tooth root development.Nakatomi M et al
    169147432006Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia.Nieuwenhuis E et al
    117840162001Ptc1 and Ptc2 transcripts provide distinct readouts of Hedgehog signaling activity during chick embryogenesis.Pearse RV 2nd et al
    146134842004Distinct roles of PTCH2 splice variants in Hedgehog signalling.Rahnama F et al
    180369962008Transcriptome analysis of differentiating spermatogonia stimulated with kit ligand.Rossi P et al
    173925012007The hedgehog signaling pathway in the mouse ovary.Russell MC et al
    145660272003Expression of hedgehog proteins in the human thymus.Sacedón R et al
    161401952005Expression patterns of hedgehog signaling peptides in naturally acquired equine osteochondrosis.Semevolos SA et al
    167074432006Lack 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
    99313361999Isolation and characterization of human patched 2 (PTCH2), a putative tumour suppressor gene inbasal cell carcinoma and medulloblastoma on chromosome 1p32.Smyth I et al
    147497652004Genomic annotation of the meningioma tumor suppressor locus on chromosome 1p34.Sulman EP et al
    169581142006Expression of hedgehog signalling components in adult mouse testis.Szczepny A et al
    161599332005Expression 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
    126265242003Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells.Wang BE et al
    158789622005Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells.Wijgerde M et al
    117587852001Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice.Yamago G et al
    155810232004Molecular 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
    100290631999PTCH2, a novel human patched gene, undergoing alternative splicing and up-regulated in basal cell carcinomas.Zaphiropoulos PG et al
    173427472007Sonic 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 IDTranscript IDUniprot
    ENSG00000117425ENST00000372192Q9Y6C5
    ENSG00000117425ENST00000438067H0Y7J2
    ENSG00000117425ENST00000447098Q9Y6C5

    Expression (GTEx)

    0
    10
    20
    30
    40
    50
    60
    Adipose - Subcutaneous
    Adipose - Visceral
    Adrenal Gland
    Artery - Aorta
    Artery - Tibial
    Bladder
    Brain - Amygdala
    Brain - Anterior cingulate cortex
    Brain - Caudate
    Brain - Cerebellar Hemisphere
    Brain - Cerebellum
    Brain - Cortex
    Brain - Frontal Cortex
    Brain - Hippocampus
    Brain - Hypothalamus
    Brain - Nucleus accumbens
    Brain - Putamen
    Brain - Spinal cord
    Brain - Substantia nigra
    Breast - Mammary Tissue
    Cells - Cultured fibroblasts
    Cells - EBV - transformed lymphocytes
    Cervix - Ectocervix
    Cervix - Endocervix
    Colon - Sigmoid
    Colon - Transverse
    Esophagus - Gastroesophageal Junction
    Esophagus - Mucosa
    Esophagus - Muscularis
    Fallopian Tube
    Heart - Atrial Appendage
    Heart - Left Ventricle
    Kidney - Cortex
    Kidney - Medulla
    Liver
    Lung
    Minor Salivary Gland
    Muscle - Skeletal
    Nerve - Tibial
    Ovary
    Pancreas
    Pituitary
    Prostate
    Skin - Not Sun Exposed
    Skin - Sun Exposed
    Small Intestine - Terminal Ileum
    Spleen
    Stomach
    Testis
    Thyroid
    Uterus
    Vagina
    Whole Blood

    Pathways

    PathwaySourceExternal ID
    Hedgehog signaling pathwayKEGGko04340
    Basal cell carcinomaKEGGko05217
    Hedgehog signaling pathwayKEGGhsa04340
    Pathways in cancerKEGGhsa05200
    Basal cell carcinomaKEGGhsa05217
    Signal TransductionREACTOMER-HSA-162582
    Signaling by GPCRREACTOMER-HSA-372790
    GPCR ligand bindingREACTOMER-HSA-500792
    Class B/2 (Secretin family receptors)REACTOMER-HSA-373080

    References

    Pubmed IDYearTitleCitations
    182854272008A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family.25
    146134842004Distinct roles of PTCH2 splice variants in Hedgehog signalling.24
    206348912010Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia.18
    234791902013Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome.15
    192376062009Genetic polymorphisms in 85 DNA repair genes and bladder cancer risk.11
    292300402018Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations.5
    192083832009A susceptibility locus on 1p32-1p34 for congenital macrostomia in a Chinese family and identification of a novel PTCH2 mutation.2
    300218652019Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms.2
    291090832018Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction.1
    192215572009[Studies on keratocystic odontogenic tumors].0

    Citation

    Peter Zaphiropoulos

    PTCH2 (patched homolog 2 (Drosophila))

    Atlas Genet Cytogenet Oncol Haematol. 2008-02-01

    Online version: http://atlasgeneticsoncology.org/gene/41892/ptch2