Nonsense-associated altered splicing of the Patched gene fails to suppress carcinogenesis in Gorlin syndrome

Abstract

Mutations in the gene coding for the transmembrane receptor protein Patched (PTCH) are implicated in the autosomal dominant disorder Gorlin syndrome (also known as naevoid basal cell carcinoma syndrome), characterized by congenital abnormalities and cancer predisposition. Tumour promotion is thought to be associated with aberrant function of PTCH, leading to misregulation of the hedgehog signalling network. However, the transcriptional events that underlie the reduced tumour suppression effects of PTCH have not been studied in detail. We describe a patient with Gorlin syndrome who had three molecular aberrations resulting in biallelic disruption of the PTCH gene, leading to abnormal protein expression and development of basal cell carcinoma. Remarkably, within tumour cells, the somatic nonsense mutation G1019X was associated with activation of a cryptic splice donor site, in which an in-frame deletion of the exon sequence containing the nonsense mutation occurred. However, the function of the resulting PTCH protein variant was still compromised. The pathogenetic alterations described give insights into the sequence of events leading to cellular transformation and underscore the importance of the PTCH protein in skin homeostasis.

TheRpe65rd12Allele Exerts a Semidominant Negative Effect on Vision in Mice

“…Previous speculation about the lack of RPE65 protein staining in the RPE suggested that the nonsense rd12 mutation might be subject to degradation by NMD. 2 This is logical, given that many RNA surveillance pathways, such as Staufenmediated mRNA decay, 52 NMD, 52,53 no-go mRNA decay, 53 and nonsense-associated altered splicing 54,55 exist in the cell to prevent the potential production of a truncated protein with a deleterious effect by a premature termination codon (PTC)containing mRNA. 53 Unfortunately, this speculation was based on immunocytochemistry data that made use of an antibody that recognized an epitope (PETLET) downstream of the nonsense mutation 2 ; even if a truncated protein was produced in rd12/rd12 mice, this antibody 2 would not be capable of detecting it.…”

Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development

“…Of note, the c.2254C>T variant corresponds to nonsense-associated altered splicing (NAS), one of the mRNA surveillance mechanisms to protect against the deleterious effects of PTCs 5 . To date, only a few cases with NAS have been reported [18][19][20][21][22] . Most of these cases caused exon skipping; however, in one case 21 , NAS created a new splice donor site similar to that in our case.…”

“…To date, only a few cases with NAS have been reported [18][19][20][21][22] . Most of these cases caused exon skipping; however, in one case 21 , NAS created a new splice donor site similar to that in our case. Our results indicate that NAS can generate a mutant protein with a unique functional property.…”

“…Moreover, our results provide evidence that an SNV can create a highly potent splice site in a genomic region, which usually has no splice site activity. However, given the limited number of previous reports [18][19][20][21][22] , generation of new exonic splice sites by SNVs, including NAS, appears to be a rare event in the human genome. Since it is known that splice site activity is determined both by the local sequence and by the genomic environment 23 , the new splice site in our case may be associated with favorable genomic circumstances.…”

Topical Treatment of Basal Cell Carcinomas in Nevoid Basal Cell Carcinoma Syndrome with a Smoothened Inhibitor

“…Consequently, Gli transcription factors get stabilized and translocate to the nucleus to induce gene transcription and thus control proliferation, survival, and differentiation of HH-responsive cells (Rohatgi and Scott, 2007;Ruiz i Altaba et al, 2007). Emergence of BCCs in NBCCS patients in general is because of somatic inactivation of the residual normal PTCH1 allele, resulting in constitutive activation of SMO and consequent uncontrolled proliferation and blockage of cellular differentiation (Laimer et al, 2008). Thus, inhibition of the HH pathway seems to be beneficial for patients suffering from this disease.…”