Conflicts of interest None declared.
Nonsense-associated altered splicing of the Patched gene fails to suppress carcinogenesis in Gorlin syndrome
Article first published online: 9 MAY 2008
© 2008 The Authors. Journal Compilation © 2008 British Association of Dermatologists
British Journal of Dermatology
Volume 159, Issue 1, pages 222–227, July 2008
How to Cite
Laimer, M., Önder, K., Schlager, P., Lanschuetzer, C.M., Emberger, M., Selhofer, S., Hintner, H. and Bauer, J.W. (2008), Nonsense-associated altered splicing of the Patched gene fails to suppress carcinogenesis in Gorlin syndrome. British Journal of Dermatology, 159: 222–227. doi: 10.1111/j.1365-2133.2008.08617.x
M.L. and K.Ö. contributed equally to this study.
- Issue published online: 9 MAY 2008
- Article first published online: 9 MAY 2008
- Accepted for publication 6 September 2007
- basal cell carcinoma;
- exon skipping;
- Gorlin syndrome;
- nonsense-associated altered splicing;
- premature stop codon
Mutations in the gene coding for the transmembrane receptor protein Patched (PTCH) are implicated in the autosomal dominant disorder Gorlin syndrome (also known as naevoid basal cell carcinoma syndrome), characterized by congenital abnormalities and cancer predisposition. Tumour promotion is thought to be associated with aberrant function of PTCH, leading to misregulation of the hedgehog signalling network. However, the transcriptional events that underlie the reduced tumour suppression effects of PTCH have not been studied in detail. We describe a patient with Gorlin syndrome who had three molecular aberrations resulting in biallelic disruption of the PTCH gene, leading to abnormal protein expression and development of basal cell carcinoma. Remarkably, within tumour cells, the somatic nonsense mutation G1019X was associated with activation of a cryptic splice donor site, in which an in-frame deletion of the exon sequence containing the nonsense mutation occurred. However, the function of the resulting PTCH protein variant was still compromised. The pathogenetic alterations described give insights into the sequence of events leading to cellular transformation and underscore the importance of the PTCH protein in skin homeostasis.