engleski

Mutation in exon 7 of PTCH deregulates SHH/PTCH/SMO signaling : Possible linkage to WNT

Clinical manifestations of an 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 might be associated with a novel constitutional mutation of PTCH gene. The novel PTCH mutation and clinical manifestations within Gorlin syndrome family links PTCH haploinsufficiency and aberrant activation of the Wnt pathway. Genetic analyses were performed on DNA samples extracted from blood leukocytes and tumor fresh or paraffin tissues including LOH (loss of heterozygosity) analysis, dHPLC and sequencing. Immunohistochemical analysis was performed on paraffin slides of tumor tissues. We found a novel constitutional mutation of PTCH gene, 1047insAGAA in exon 7 leading to termination of Ptch protein at exon 9. The family tumors we analyzed show extensive LOH in the PTCH region, both basocellular and in particular craniopharyngioma, and in the latter 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.

craniopharyngioma ; Gorlin syndrome ; constitutional mutation ; PTCH gene ; Sss/Ptch/Smo and Wnt pathway ; Ptch ; tumor suppressor

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