Ppp2r5d-flox Mouse

Ppp2r5d, encoding the protein PPP2R5D (also known as the B56 delta subunit), is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). PP2A, along with protein phosphatase 1 (PP1), accounts for over 90% of all phospho-serine/threonine dephosphorylations in different tissues. The PPP2A-PPP2R5D holoenzyme is crucial for maintaining neurons, regulating neuronal signaling, and is highly expressed in the brain [2].

Germline de novo mutations in the PPP2R5D gene lead to PPP2R5D-related intellectual disability (ID) and neurodevelopmental delay. Clinical signs include ID, autism spectrum disorder (ASD), epilepsy, speech problems, and various malformations [2]. A study on 76 individuals with PPP2R5D variants found common phenotypes such as language, intellectual or learning disabilities, hypotonia, macrocephaly, seizures, and ASD. Functional analysis of pathogenic variants revealed impaired PP2A A/C-subunit binding, decreased short-linear interaction motif-dependent substrate binding, or both, supporting a dominant-negative disease mechanism [1]. Some individuals also presented with early-onset parkinsonism, expanding the clinical spectrum of PPP2R5D-related disorders [3,5]. Additionally, PPP2R5D has been shown to promote hepatitis C virus infection by binding to viral NS5B and enhancing viral RNA replication [4].

In conclusion, Ppp2r5d is essential for normal neurodevelopment as its mutations lead to a range of neurodevelopmental disorders. The study of Ppp2r5d-related mutations in individuals has provided insights into the molecular mechanisms underlying these disorders, highlighting its importance in neuronal function and disease etiology. Also, its role in viral infection adds another dimension to its biological significance.