title: Nonsense-associated altered splicing of the Patched gene fails to suppress carcinogenesis in Gorlin syndrome.
abstract: 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.
authors.affiliation: Division of Molecular Dermatology, Department of Dermatology, General Hospital Salzburg, Paracelsus Private Medical University Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Laimer
authors.forename: K
authors.initials: K
authors.lastname: Onder
authors.forename: P
authors.initials: P
authors.lastname: Schlager
authors.forename: C M
authors.initials: CM
authors.lastname: Lanschuetzer
authors.forename: M
authors.initials: M
authors.lastname: Emberger
authors.forename: S
authors.initials: S
authors.lastname: Selhofer
authors.forename: H
authors.initials: H
authors.lastname: Hintner
authors.forename: J W
authors.initials: JW
authors.lastname: Bauer
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D001478:Basal Cell Nevus Syndrome / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D004273:DNA, Neoplasm; D053823:Hedgehog Proteins; D008565:Membrane Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D044102:Receptor, Melanocortin, Type 1; D011956:Receptors, Cell Surface