CRISPR-pass: Gene rescue of nonsense mutations using adenine base editors

Abstract

A nonsense mutation is a substitutive mutation in a DNA sequence that causes a premature termination during translation and produces stalled proteins resulting in dysfunction of a gene. Although it usually induces severe genetic disorders, there are no definite methods for inducing read-through of premature termination codons (PTCs). Here, we present a targeted tool for bypassing PTCs, named CRISPR-pass that uses CRISPR-mediated adenine base editors. CRISPR-pass, which should be applicable to 95.5% of clinically significant nonsense mutations in the ClinVar database, rescues protein synthesis in patient-derived fibroblasts, suggesting potential clinical utility.