DHPLC Analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novel<i>PTCH</i>missense mutations in the sterol-sensing domain

Marsh, Anna; Wicking, Carol; Wainwright, Brandon; Chenevix-Trench, Georgia

doi:10.1002/humu.9365

Cited by 33 publications

(23 citation statements)

References 23 publications

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“…In addition, this mutation is located in sterol-sensing domain associated with trafficking of many proteins including Hedgehog [6], suggesting this domain might play another important role in NBCCS as suggested in a previous report [7].…”

supporting

confidence: 54%

A novel PTCH1 mutation in a patient of nevoid basal cell carcinoma syndrome

Honma

Ohishi

Uehara

et al. 2008

Journal of Dermatological Science

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supporting

confidence: 54%

A novel PTCH1 mutation in a patient of nevoid basal cell carcinoma syndrome

Honma

Ohishi

Uehara

et al. 2008

Journal of Dermatological Science

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“…According to the publicly available PTCH1 mutation database (http://www.cybergene.se/PTCH/), more than 160 PTCH1 mutations in patients with NBCCS have been accumulated. However, despite extensive efforts to detect mutations, using single strand conformation polymorphism, PCR-direct sequencing of all exons or denaturing high performance liquid chromatography, mutations are still unidentified in 25-60% of patients (Fujii et al 2003;Marsh et al 2005;Lindström et al 2006). In these cases, the PTCH1 mutations may be in regulatory regions, or may involve large deletions.…”

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confidence: 99%

High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome

et al. 2007

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Small submicroscopic genomic deletions and duplications constitute up to 15% of all mutations underlying human monogenic diseases. In this study, we used newly designed high-resolution oligonucleotide microarrays with a median distance between the probes of 776 bp (average probe interval 2,271 bp) to detect gene deletions in nevoid basal cell carcinoma syndrome (NBCCS) patients. NBCCS, also called Gorlin syndrome, is characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the human patched-1 (PTCH1) gene. Two out of three deletions could not be detected by a conventional chromosomal analysis. A submicroscopic deletion as small as 165 kb was detected affecting only PTCH1, whereas the other two deletions were much larger (5 and 11 Mb). We demonstrated not only the exact number of genes involved in the deletion but also rapidly determined the junction sequences after pinpointing the breakpoint regions in all individuals analyzed. This report of an array-based determination of junction sequences of long deletions circumvented a labor-intensive analysis such as Southern blotting or FISH. Alu-mediated recombination in one case and non-homologous end joining in the other two were probably implicated in the generation of deletions. This method will contribute to the understanding of molecular pathogenesis of gene deletions as well as rapid genetic testing.

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“…The PTCH mutation frequency in NBCCS patients reported varies considerably in the different studies, ranging from 40 to 80% (Kimonis et al, 2004;Marsh et al, 2005).…”

mentioning

confidence: 99%

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

et al. 2006

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The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis p40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common.

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DHPLC Analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novelPTCHmissense mutations in the sterol-sensing domain

Cited by 33 publications

References 23 publications

A novel PTCH1 mutation in a patient of nevoid basal cell carcinoma syndrome

A novel PTCH1 mutation in a patient of nevoid basal cell carcinoma syndrome

High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome

PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

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