Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the patched-1 (PTCH1) gene. To date, we have detected 73 mutations in PTCH1 and ten of them (14 %) were suspected splicing mutations. Eight out of the ten mutations were localized near the splice donor site. Five mutations were localized within the invariant GT-AG splice site, whereas the other five mutations occurred outside the invariant GT-AG site including the last exonic nucleotide. When the transcripts were examined, all mutations resulted in aberrant splicing, including exon skipping or the activation of cryptic splice sites. This is the first extensive report of NBCCS focusing on splice site mutations, and it highlights the importance of analyzing transcripts especially for mutations lying outside the GT-AG splicing consensus site. In addition, the splice site score calculated by Splice-Site Analyzer Tool provided by Tel Aviv University helped predict aberrant splice patterns in most of the cases.
KeywordsNevoid basal cell carcinoma syndrome PTCH1 Splicing mutation
The authors acknowledge the cooperation of the attending physicians in this study. This study was supported by Ministry of Education, Culture, Sports, Science and Technology of Japan Grant-in-Aid for Scientific Research (KAKENHI) 26461530 (to T. M.), 15K19041 (to K. N.) and 16K09960 (Katsunori Fujii) and by a grant from Kitasato University Graduate School of Medical Sciences (Integrative Research Program 2015–2016) (to T. M.).
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