Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a pleiotropic, autosomal dominant disease. Growing evidence suggests that the disorder may result from mutations in genes of the Sonic hedgehog (Shh) signalling pathway. Objective: The present study aimed to investigate the pathogenic gene in a Chinese Han NBCCS family.
Methods: Mapping and mutation screening were used to investigate the candidate genes SHH, PTCH, PTCH2, and SMO. A GLI1 reporter gene and cell growth curve were used to examine functional consequences of the detected mutant.
Results: One novel mutation, a G-to-A transition (2157G>A) in exon 15 of the PTCH2 gene, was identified in this NBCCS family by direct sequencing and was detected with the AvaI restriction enzyme. The mutation was not observed in normal family members or in 520 controls. The mutation led to an R719Q amino acid substitution in an extracellular loop of the PTCH2 protein. Functional studies revealed that the R719Q mutation resulted in inactivation of PTCH2 inhibitory activities. In contrast to wild type PTCH2, PTCH2-R719Q could not inhibit cell proliferation.
Conclusion: PTCH2 (2157G>A), a novel missense mutation underlies NBCCS that results in the loss of PTCH2 inhibitory function in the Shh signalling pathway.
- loss of function
- missense mutation
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