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

Sandra Luna, Leire Torices, Janire Mingo, Laura Amo, Isabel Rodríguez‐Escudero, Pablo Ruiz‐Ibarlucea, Asier Erramuzpe, Jesús M. Cortés, María I. Tejada, María Molina, Caroline E. Nunes‐Xavier, José I. López, Víctor J. Cid, and Rafael Pulido. A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons. Human Mutation. In press, 2021 [pdf]

Abstract
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.

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