Disease relevance of PTCH1

• Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS) [1].
• In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas [1].
• According to this model, the inhibition of SMO signalling is relieved following mutational inactivation of PTCH in basal-cell nevus syndrome [2].
• Basal cell carcinomas, the commonest human skin cancers, consistently have abnormalities of the hedgehog signaling pathway and often have PTCH gene mutations [3].
• Insight into their genesis came from identification of mutations in the PATCHED gene (PTCH) in patients with the basal-cell nevus syndrome, a hereditary disease characterized by multiple BCCs and by developmental abnormalities [2].

High impact information on PTCH1

• Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH) [1].
• The membrane protein Patched1 (Ptc1), which controls cell fate in many tissues, regulates cell growth in the cerebellum, and reduced Ptc1 function contributes to medulloblastoma [4].
• Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH) [5].
• Ptc1p, a serine/threonine phosphatase, has previously been shown to regulate mitochondrial inheritance by an unknown mechanism [6].
• Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene [7].

Chemical compound and disease context of PTCH1

• DHPLC analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novel PTCH missense mutations in the sterol-sensing domain [8].
• When only patients with basal cell nevus syndrome ( BCNS ) or basal cell carcinoma (BCC) who had never received retinoid were compared with those who received isotretinoin, the frequency of the defined abnormalities was significantly higher in the treated group (P less than 0.01) [9].

Biological context of PTCH1

• In order to examine the phenotypic variability in NBCCS and to highlight functionally important domains of the PTCH protein, we have now screened 71 unrelated NBCCS individuals for mutations in the PTCH exons [10].
• Two missense mutations have been identified, and their location within transmembrane domains supports the notion that PTCH may have a transport function [10].
• Recently, PTCH2, a molecule with sequence homology to PTCH, has been identified [11].
• Detecting tissue-specific alternative splicing and disease-associated aberrant splicing of the PTCH gene with exon junction microarrays [12].
• Whereas Gorlin's syndrome patients carry germ-line mutations in the patched (PTCH) gene, Turcot's syndrome patients with MBs carry germ-line mutations of the adenomatous polyposis coli (APC) gene [13].

Anatomical context of PTCH1

• While PTCH is expressed throughout the mouse embryo, PTCH2 is found at high levels in the skin and in spermatocytes [11].
• About one-third of sporadic basal cell carcinomas (BCCs) of the skin and 10-15% of primitive neuroectodermal tumors (PNETs) of the central nervous system show mutations in the PTCH tumor suppressor gene [14].
• Normal urothelium and TCC cell lines express these three genes within the PTCH signal transduction pathway [15].
• We then screened for PTCH mutations in 'hot spot' exons 6, 8, 13 and 16 by PCR/SSCP analysis of genomic DNAs from 54 TCC tumor samples and control autologous peripheral blood lymphocytes [15].
• SHH was expressed at the top of the crypts and in a few basally located cells, while PTCH was detected in the neuroendocrine cells and SMOH at the brush border of superficial epithelium [16].

Associations of PTCH1 with chemical compounds

• CONCLUSIONS: Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS [17].
• In the two missense mutations, the strong basic residue arginine was substituted by serine or glycine in highly conserved components of the putative transmembrane domain of PTCH, and these mutations may therefore affect the conformation and function of the PTCH protein [18].
• We analyzed loss of heterozygosity (LOH) at five markers in and around the PTCH gene in 276 keratinocyte tumors from a population-based study in New Hampshire. We found a high prevalence of any 9q22.3 LOH in both BCC (75.5%) and SCC (60.8%), with BCC being significantly more likely to have LOH than SCC (P<0.009) [19].
• No abnormalities in the human homologue of the Drosophila segment polarity gene patched (PTCH), glutathione S-transferases T1 and M1, or cytochrome P450 1A1 were detected by polymerase chain reaction (PCR)-based molecular analysis [20].
• The localization of a CGG/CCG repeat in PTCH is quite unique in that only four other genes have been found in which the repeat is localized up to 4 bp upstream of the first methionine [21].

Physical interactions of PTCH1

• This repression is relieved when SHH binds to PTCH [22].
• The functional part of SNX17 that binds P-selectin or Patched (PTCH) consists of a truncated FERM domain and a unique C terminus together (FC-unit) [23].

Regulatory relationships of PTCH1

• Additionally, deletion mapping of PTCH1 has revealed that the domains encompassed by amino acids 180-786 and 1058-1210 are of highest significance in inhibiting GLI1 gene activation [24].
• It now appears that constitutive activation of Hedgehog signalling, by inactivating mutations in PTCH1 or activating mutations in the coreceptor SMOH, is required and possibly sufficient for basal cell carcinoma development and also contributes to the formation of a variety of other tumour types, including medulloblastoma and rhabdomyosarcoma [25].
• These findings suggest that PTCH mutations represent an earlier event in BCC development than p53 alterations and that the inability of XP patients to repair UV-induced PTCH mutations might significantly contribute to the early and frequent appearance of BCC observed in these patients [26].
• PHS mutant protein (GLI3-PHS) localizes to the nucleus and represses GLI3-activated PTCH1 expression, which is similar to Ci75 [27].
• Here, we show that RET/PTC1 activates the Rap1 small GTPase [28].

Other interactions of PTCH1

• The majority of tumors showed an increased expression of SMOH, PTCH, and GL11 transcripts as compared with that of normal skin and nonneoplastic brain tissue, respectively [14].
• Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations [29].
• RESULTS: No patient had a mutation in PTEN or PTCH [17].
• Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling [30].
• Four of nine informative fetal rhabdomyomas and embryonal rhabdomyosarcomas showed loss of heterozygosity (LOH) in the PTCH region with two of these (one fetal rhabdomyoma and one embryonal rhabdomyosarcoma) also showing LOH in the SUFU region [30].

Analytical, diagnostic and therapeutic context of PTCH1

• To monitor splicing events of the PTCH gene, we designed oligonucleotide arrays on which exon probes and exon-exon junction probes as well as a couple of intron probes for the PTCH gene were placed in duplicate [12].
• We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas [31].
• Moreover, molecular epidemiology composed of incidence of p53 and PTCH mutations, difference in the type of mutation and repair bias of UV-induced DNA lesions might affect the distinct features of BCCs between different racial population [32].
• INVESTIGATIONS: Physical examination, karyotyping, abdominal and pelvic ultrasound, brain CT scan, anatomic pathology analysis with immunohistochemistry, and typing of polymorphic markers in the patched (PTCH) gene region [33].
• In contrast, RET/PTC1 microinjection induced NE irregularity in 27% of cells at 6 hours and 37% of cells at 18 to 24 hours [34].

References