title: Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling: possible linkage to WNT.
abstract: The novel PTCH mutation and clinical manifestations within Gorlin syndrome family links PTCH haploinsufficiency and aberrant activation of the Wnt pathway. We report a family case with Gorlin syndrome, characterized by the usual phenotype features such as widespread basocellular tumors and craniofacial and bone malformations, but also including a less common appearance of craniopharyngioma. These clinical manifestations might be associated with a novel constitutional mutation of the PTCH gene, 1047insAGAA, which we found in exon 7. It changes the normal amino acid sequence leading to termination of the PTCH protein at exon 9. The analyzed tumors of the family show extensive loss of heterozygosity in the PTCH region, both basocellular and in particular craniopharyngioma, and in the latter a high expression of beta-catenin was detected. Our findings suggest involvement of the SHH/PTCH/SMO pathway in pathogenesis of the analyzed disorders, including its possible contribution to aberrant activation of the Wnt pathway in craniopharyngioma.
authors.affiliation: Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
authors.forename: Vesna
authors.initials: V
authors.lastname: Musani
authors.forename: Philippe
authors.initials: P
authors.lastname: Gorry
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Basta-Juzbasic
authors.forename: Tonci
authors.initials: T
authors.lastname: Stipic
authors.forename: Pavle
authors.initials: P
authors.lastname: Miklic
authors.forename: Sonja
authors.initials: S
authors.lastname: Levanat
mesh_terms: D000595:Amino Acid Sequence; D001478:Basal Cell Nevus Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D002648:Child; D003397:Craniopharyngioma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics*; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D053823:Hedgehog Proteins; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D015534:Trans-Activators; D051153:Wnt Proteins