A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons

The PTEN tumor suppressor gene is mutated with high incidence in tumors and in the germline of patients with cancer predisposition or with macrocephaly associated with autism. PTEN nonsense mutations generating premature termination codons (PTC) and producing nonfunctional truncated PTEN proteins are frequent in association with human disease. However, there are no studies addressing the restoration of full-length PTEN proteins from the PTC-mutated PTEN gene by translational readthrough. Here, we have performed a global translational and functional readthrough analysis of the complete collection of PTEN PTC somatic or hereditary mutations found in tumors or in the germline of patients (disease-associated PTEN PTCome), and we set standards for the analysis of the potential of readthrough functional reconstitution in disease-relevant genes. Our analysis indicates that prevalent pathogenic PTEN PTC mutations are susceptible to PTEN functional restoration in response to readthrough-inducing compounds. Comprehensive readthrough analyses of disease-associated PTComes will be valuable tools for the implementation of readthrough-based precision interventions in specific groups of patients.

Automated summary

The PTEN tumor suppressor gene is frequently mutated in tumors and in cancer predisposition patients or those with macrocephaly associated with autism. A study has analyzed PTEN nonsense mutations and set standards for the potential restoration of full-length PTEN proteins from mutated PTEN genes through translational readthrough. The findings indicate that prevalent pathogenic PTEN mutations can be functionally restored through readthrough-inducing compounds, offering potential for precision interventions in specific patient groups.