Pus3-flox Mouse

Pus3, or pseudouridine synthase 3, is an enzyme that catalyzes pseudouridylation of position 38/39 in tRNAs, playing a critical role in tRNA structure, function, and stability [1,3]. Pseudouridine (Ψ) is an isomer of uridine, ubiquitously present in RNA such as tRNA, rRNA, and mRNA [1]. Understanding Pus3 function can be facilitated by genetic models like gene knockout (KO) models.

Genomic mutations in PUS3 have been identified in patients with neurodevelopmental disorders. For instance, certain mutations in PUS3, such as p.Tyr71Cys and p.Ile299Thr, can lead to reduced protein thermostability, aggregation, and decreased PUS3-dependent Ψ levels in patient fibroblasts, thus explaining the observed clinical phenotypes [2]. Biallelic pathogenic variants of PUS3 are associated with severe intellectual disability, microcephaly, epilepsy, short stature, and other phenotypes, expanding the phenotypic spectrum of PUS3-related disorders [3,4]. In yeast, absence of the homologous Deg1/Pus3 results in increased lipid droplet content, translational defects, and lipidome remodeling, indicating its role in coordinating lipid storage and mobilization [5].

In conclusion, Pus3 is essential for tRNA modification, with its dysfunction linked to various neurodevelopmental and other disorders. Studies using genetic models, though not specifically KO/CKO mouse models in the provided references, have helped uncover its role in biological processes and disease conditions, offering insights into the molecular mechanisms underlying these diseases.