Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Patched-one or smoothened gene mutations are infrequent in chondrosarcoma.

ABSTRACT: Constitutive hedgehog signaling has been implicated in the tumorigenesis of cartilaginous neoplasia; however, a common mutational mechanism remains unknown. Some tumors exhibiting hedgehog pathway activation such as basal cell cancer frequently harbor PATCHED-ONE (PTCH-1) or SMOOTHENED (SMO) gene mutations. We therefore asked whether mutations of the hedgehog receptor genes PTCH-1 or SMO occur in cartilage tumors. Singlestrand conformation polymorphism (SSCP) analysis with subsequent manual sequencing was performed to detect alterations of PTCH-1 and SMO in 46 cartilage tumors. SSCP detected five shifts in the PTCH-1 gene and two shifts in SMO. Direct DNA sequencing revealed the five shifts in PTCH-1 were caused by silent nucleotide alterations. The two SMO shifts were the result of the same missense mutation (783G>A) and occurred in one dedifferentiated chondrosarcoma and a synovial chondromatosis. The patient with chondromatosis also carried this same mutation in the germline. However, this mutation was also identified in leukocyte DNA from three of 127 (2.4%) control subjects without cartilage tumors, suggesting it may represent a rare SMO variant. Constitutive activation of the hedgehog signaling pathway in chondrosarcoma is rarely caused by PTCH-1 or SMO mutations. [corrected]

SUBMITTER: Yan T

PROVIDER: S-EPMC2492993 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion.

Project description:The developmentally important hedgehog (Hh) pathway is activated by binding of Hh to patched (Ptch1), releasing smoothened (Smo) and the downstream transcription factor glioma associated (Gli) from inhibition. The mechanism behind Ptch1-dependent Smo inhibition remains unresolved. We now show that by mixing Ptch1-transfected and Ptch1 small interfering RNA-transfected cells with Gli reporter cells, Ptch1 is capable of non-cell autonomous repression of Smo. The magnitude of this non-cell autonomous repression of Smo activity was comparable to the fusion of Ptch1-transfected cell lines and Gli reporter cell lines, suggesting that it is the predominant mode of action. CHOD-PAP analysis of medium conditioned by Ptch1-transfected cells showed an elevated 3beta-hydroxysteroid content, which we hypothesized to mediate the Smo inhibition. Indeed, the inhibition of 3beta-hydroxysteroid synthesis impaired Ptch1 action on Smo, whereas adding the 3beta-hydroxysteroid (pro-)vitamin D3 to the medium effectively inhibited Gli activity. Vitamin D3 bound to Smo with high affinity in a cyclopamine-sensitive manner. Treating zebrafish embryos with vitamin D3 mimicked the smo(-/-) phenotype, confirming the inhibitory action in vivo. Hh activates its signalling cascade by inhibiting Ptch1-dependent secretion of the 3beta-hydroxysteroid (pro-)vitamin D3. This action not only explains the seemingly contradictory cause of Smith-Lemli-Opitz syndrome (SLOS), but also establishes Hh as a unique morphogen, because binding of Hh on one cell is capable of activating Hh-dependent signalling cascades on other cells.

| S-EPMC1502141 | biostudies-literature

Subcellular distribution of patched and smoothened in the cerebellar neurons.

Project description:The Sonic hedgehog (Shh) signaling pathway carries out a wide range of biological functions such as patterning of the embryonic neural tube and expansion of cerebellar granule cell precursors. We previously have found that the Shh signaling receptors, Patched1 (Ptch1) and Smoothened (Smo), are expressed in hippocampal neurons of developing and adult rats, suggesting the continued presence of Shh signaling in postmitotic, differentiated neurons. Here, we report that Ptch1 and Smo are present in the processes and growth cones of immature neurons in the developing cerebellum, and that, in the mature cerebellum, Ptch1 and Smo are expressed by several types of neurons including Purkinje cells, granule cells, and interneurons. Within these neurons, Ptch1 and Smo are predominantly localized in the postsynaptic side of the synapses, a distribution pattern similar to that found in hippocampal neurons. Our findings provide morphological evidence that Shh signaling events are not confined to neuronal precursors and are likely to have ongoing roles within the postmitotic neurons of the developing and adult cerebellum.

| S-EPMC3495249 | biostudies-literature

Structures of vertebrate Patched and Smoothened reveal intimate links between cholesterol and Hedgehog signalling.

Project description:The Hedgehog (HH) signalling pathway is a cell-cell communication system that controls the patterning of multiple tissues during embryogenesis in metazoans. In adults, HH signals regulate tissue stem cells and regenerative responses. Abnormal signalling can cause birth defects and cancer. The HH signal is received on target cells by Patched (PTCH1), the receptor for HH ligands, and then transmitted across the plasma membrane by Smoothened (SMO). Recent structural and biochemical studies have pointed to a sterol lipid, likely cholesterol itself, as the elusive second messenger that communicates the HH signal between PTCH1 and SMO, thus linking ligand reception to transmembrane signalling.

| S-EPMC6744280 | biostudies-literature

Patched 1 regulates Smoothened by controlling sterol binding to its extracellular cysteine-rich domain.

Project description:Smoothened (SMO) transduces the Hedgehog (Hh) signal across the plasma membrane in response to accessible cholesterol. Cholesterol binds SMO at two sites: one in the extracellular cysteine-rich domain (CRD) and a second in the transmembrane domain (TMD). How these two sterol-binding sites mediate SMO activation in response to the ligand Sonic Hedgehog (SHH) remains unknown. We find that mutations in the CRD (but not the TMD) reduce the fold increase in SMO activity triggered by SHH. SHH also promotes the photocrosslinking of a sterol analog to the CRD in intact cells. In contrast, sterol binding to the TMD site boosts SMO activity regardless of SHH exposure. Mutational and computational analyses show that these sites are in allosteric communication despite being 45 angstroms apart. Hence, sterols function as both SHH-regulated orthosteric ligands at the CRD and allosteric ligands at the TMD to regulate SMO activity and Hh signaling.

| S-EPMC9166294 | biostudies-literature

New mutations and an updated database for the patched-1 (PTCH1) gene.

Project description:BACKGROUND:Basal cell nevus syndrome (BCNS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), maxillary keratocysts, and cerebral calcifications. BCNS most commonly is caused by a germline mutation in the patched-1 (PTCH1) gene. PTCH1 mutations are also described in patients with holoprosencephaly. METHODS:We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). We included 117 new PTCH1 variations, in addition to 331 previously published unique PTCH1 mutations. These new mutations were found in 141 patients who had a positive PTCH1 mutation analysis in either the VU University Medical Centre (VUMC) or Maastricht University Medical Centre (MUMC) between 1995 and 2015. RESULTS:The database contains 331 previously published unique PTCH1 mutations and 117 new PTCH1 variations. CONCLUSION:We have established a locus-specific database for the PTCH1 gene using the Leiden Open Variation Database (LOVD). The database provides an open collection for both clinicians and researchers and is accessible online at http://www.lovd.nl/PTCH1.

| S-EPMC6014442 | biostudies-literature

Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover.

Project description:Hedgehog signaling plays conserved roles in controlling embryonic development; its dysregulation has been implicated in many human diseases including cancers. Hedgehog signaling has an unusual reception system consisting of two transmembrane proteins, Patched receptor and Smoothened signal transducer. Although activation of Smoothened and its downstream signal transduction have been intensively studied, less is known about how Patched receptor is regulated, and particularly how this regulation contributes to appropriate Hedgehog signal transduction. Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. Moreover, we showed that Smurf-mediated Patched ubiquitination depends on Smo activity in wing discs. Mechanistically, we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc. The further mathematic modeling analysis reveals that a bidirectional control of activation of Smo involving Smurf and Patched is important for signal-receiving cells to precisely interpret external signals, thereby maintaining Hedgehog signaling reliability. Finally, our data revealed an evolutionarily conserved role of Smurf proteins in controlling Hh signaling by targeting Ptc during development.

| S-EPMC3841102 | biostudies-literature

IDH1/2 Mutations Predict Shorter Survival in Chondrosarcoma.

Project description:Background. Recent studies have shown that isocitrate dehydrogenase 1/2 (IDH1/2)- activating mutations occur in a variety of cancers, including acute myeloid leukaemia, gliomas, and chondrosarcomas (CHS)s. The effect of IDH1/2 mutation on overall survival (OS) has not been reported in CHS. The aim of our study was to assess the prevalence of known cancer-related gene mutations in CHS, as well as their prognostic role in patient survival. Methods. DNA from FFPE samples of 80 patients (F:M- 1:1.3; mean age: 58 years; range 27-86) with histologically confirmed CHS (G1:29; G2:34; G3:17) was subjected to library preparation with the Ion AmpliSeq Cancer Hotspot Panel v2 and sequenced on the PGM Ion Torrent. Results. Among the clinical features only histological grade influenced OS. Deep sequencing identified 1784 single nucleotide variants. Of them, 426 were considered to be pathogenic or probably pathogenic. Activating IDH1/2 mutations were found in 27 patients (34%) including 17 R132 IDH1 (21%), 10 R172 IDH2 (13%) and 3 R140 IDH2 variants (4%). Three patients had concurrent IDH1 and IDH2 mutations. The R140 IDH2 mutant has not been reported to date in CHS patients. OS for CHS patients with IDH1/2 mutations was significantly lower than in patients without mutations (93% vs 64%; p<0.001). No other genetic feature of the Cancer Hotspot Panel had an impact on OS. Conclusions. In CHS, IDH1/2-mutation status and the histological aggressiveness of the CHS are important predictors for OS. The R140 IDH2 may also be a novel target for the treatment of CHS patients.

| S-EPMC5868167 | biostudies-literature

Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.

Project description:ObjectiveMutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia.MethodsWe sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes.ResultsIn erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations.ConclusionsTwo novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.

| S-EPMC3594382 | biostudies-literature

DICER1 RNase IIIb domain mutations are infrequent in testicular germ cell tumours.

Project description:BACKGROUND: Testicular Germ Cell Tumours (TGCT) are the most frequently occurring malignancy in males from 15-45 years of age. They are derived from germ cells unable to undergo physiological maturation, although the genetic basis for this is poorly understood. A recent report showed that mutations in the RNase IIIb domain of DICER1, a micro-RNA (miRNA) processing enzyme, are common in non-epithelial ovarian cancers. DICER1 mutations were found in 60% of Sertoli-Leydig cell tumours, clustering in four codons encoding metal-binding sites. Additional analysis of 14 TGCT DNA samples identified one case that also contained a mutation at one of these sites. FINDINGS: A number of previous studies have shown that DICER1 mutations are found in <1% of most cancers. To provide a more accurate estimate of the frequency of such mutations in TGCTs, we have analysed 96 TGCT samples using high resolution melting curve analysis for sequence variants in these four codons. Although we did not detect any mutations in any of these sites, we did identify a novel mutation (c.1725 R>Q) within the RNase IIIb domain in one TGCT sample, which was predicted to disturb DICER1 function. CONCLUSION: Overall our findings suggest a mutation frequency in TGCTs of ~1%. We conclude therefore that hot-spot mutations, frequently seen in Sertoli-Leydig cell tumours, are not common in TGCTs.

| S-EPMC3503615 | biostudies-literature

Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome.

Project description:AimTo search for patched homologue 1 (PTCH1) mutations in four families with basal cell nevus syndrome (BCNS).MethodsMutation analysis of PTCH1 in unrelated Japanese families affected with BCNS was carried out by direct sequencing.ResultsSix novel PTCH1 mutations, 833G-->A in exon 6, 1415C-->A and 1451G-->T in exon 10, 2798delC in exon 17, 2918-2925dupAGTTCCCT in exon 18 and 3956C-->A in exon 23, were identified.ConclusionsAmong the six PTCH1 mutations, two frameshift mutations (2798delC and 2918-2925dupAGTTCCCT) and one nonsense mutation (833G-->A) are predicted to lead to premature termination of PTCH1 protein translation. Three simultaneous mutations, 1415C-->A (A472D) and 1451G-->T (G484V) in exon 10, and 3956G-->A (R1319H) in exon 23, were found on one allele in only affected members in one family and none of them were found among 90 unrelated healthy Japanese. The three mutations on one chromosome may have resulted from errors in the recombinational repair process and this is the first report on the PTCH1 mutations due to such a mechanism.

| S-EPMC1861741 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data