Selective haploinsufficiency of longer isoforms of PTCH1 protein can cause nevoid basal cell carcinoma syndrome

Abstract

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The PTCH1 gene has five alternatively used first exons resulting in the translation of three isoforms of the PTCH1 protein; that is, PTCHL, PTCHM and PTCHS. However, the biological significance of each isoform is unclear. Here we show an individual with NBCCS carrying a nonsense mutation in PTCH1 exon2, c.387G4A (p.W129X). As the mutation lay upstream of the ATG codon used for PTCHS translation, the mutant allele still expressed RNA isoforms that encode PTCHS. These results clearly demonstrate that a selective haploinsufficiency of longer isoforms of the PTCH1 protein, PTCHL and PTCHM, but not PTCHS is sufficient to cause NBCCS. Although mice selectively deficient in PTCHS isoforms are currently unavailable, this study sheds light on the complex in vivo roles of PTCH1 isoforms.

PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

“…aThis mutation has been reported in a holoprosencephaly patient [40].bThis mutation has been reported in a NBCCS patient [41].cThis mutation has been reported in a NBCCS patient [42].dThose patients suffered from cleft lip or plate.Abbreviations: NB, NBCCS.…”

Case Report Multiple nevoid basal cell carcinoma syndrome associated with congenital orbital teratoma, caused by a PTCH1 frameshift mutation

“…We hypothesize that this rare phenotype likely results from the shortened and nonfunctional truncated PTCH1 protein (p.Asn97LysfxX43), which is expressed from the mutated allele (c.290dupA). To date, more than 80% of reported PTCH1 mutations responsible for NBCCS are nonsense, splice site, insertion, deletion, or duplication mutations that lead to expression of nonfunctional truncated proteins (Boutet et al, 2003;Lo Muzio, 2008), some of which have been confirmed experimentally (Fujii et al, 2003;Pastorino et al, 2005;Pan et al, 2010;Suzuki et al, 2012). These mutations spread along the PTCH1 gene with no preferential hotspot and can arise by several mechanisms.…”

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

“…The expression of the transcript 1b is specifically induced in nodular basal cell carcinoma (BCC). 15,19 Transcripts 1b and 1c harbor in their promoter one active Gli-consensus binding site, which upon HH stimulation affects their specific expression. 20 The PTCH1 gene is suggested to be a tumor suppressor, and inactivating germline mutations of PTCH1 cause basal cell nevus syndrome (BCNS) (MIM 109400).…”

“…23 Most of the malformations are caused by PTCH1 haploinsufficiency, indicating that the physiological pathway activity is sensitive to relatively small changes in PTC1 levels. 19,24 One of the main roles of 5' untranslated region (5'UTR) of mRNAs is post-transcriptional regulation of gene expression, starting from the initiation of protein translation. [25][26][27] The 5'UTRs can differ in length, nucleotide content, secondary structures, and the presence of different functional elements.…”