Objective: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a predisposition to neoplasms and developmental abnormalities. Mutation of the PTCH1 gene, which is considered to be responsible for NBCCS, was investigated in a Chinese NBCCS family in this study. Methods: Genomic DNA was isolated from blood samples of all eight living individuals in this family. Mutation analysis of PTCH1 was done by amplified polymerase chain reaction and direct sequencing. Biophysical predictions of the altered protein were made using various bioinformatics tools. To determine the action of the mutated protein, the expression of Gli1 and Gli2 was investigated by immunohistochemistry. Results: A novel PTCH1 mutation at 897G -> A in exon4 was identified in all four affected members. This mutation was not found in any unaffected members of this family or in 100 unrelated healthy Chinese people. The mutation causes amino acid replacement 237E -> K in the first large extracellular loop of the PTCH1 protein which is required for Sonic Hedgehog (Shh) binding. This mutation changes the protein's biochemical properties and protein activity, resulting in subsequent activation of transcription factors, Gli1 and Gli2, in the Shh/Gli signaling pathway. Immunohistochemistry showed overexpression of Gli1 and Gli2 in the keratocystic odontogenic tumor (KCOT) tissues. (C) 2011 Published by Elsevier Inc.