PPP2R5E: New gene potentially involved in specific learning disorders and myopathy

• Published in: Gene Vol. 933; p. 148945
• Main Authors: Musumeci, Antonino, Vinci, Mirella, Verbinnen, Iris, Treccarichi, Simone, Nigliato, Eleonora, Chiavetta, Valeria, Greco, Donatella, Vitello, Girolamo Aurelio, Federico, Concetta, Janssens, Veerle, Saccone, Salvatore, Calì, Francesco
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.01.2025
• Subjects: amino acids; B56ε; brain; Exome Sequencing; family; genes; heterozygosity; Humans; Hypotonia; Learning Disabilities - genetics; Male; muscular diseases; Muscular Diseases - genetics; Mutation; Myopathy; Neurodevelopmental delay; phosphoprotein phosphatase; PP2A; PPP2R5E; Protein Phosphatase 2 - genetics; risk; BB; WES; MRI; MTCL1; GDD; SLD; Neurodevelopmental delay; aCGH; ASD; QMUP; Hypotonia; PPP2R5E; ID; EMG; ACMG; AD; MT; OMIM; PPP2R5B; MUP; PP2A; PPP2R5C; B56ε; VL; HGMD; IGV; IPA; NGS; Myopathy; ENG
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148945

•A de novo variant of PPP2R5E gene potentially linked to specific learning disorders.•First report of a link between PPP2R5E gene and specific learning disorders.•The variant Glu191Lys was identified within a conserved motif on PPP2R5 B-subunits.•Increased spectrum of PP2A-related disease genes. Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures. In the current work, we present an individual with specific learning problems, motor coordination disorders, hypotonia and behavioural issues. Although whole exome sequencing (WES) did not unveil pathogenic variants in known genes related to these symptoms, a de novo heterozygous variant Glu191Lys was identified within PPP2R5E, encoding the PP2A regulatory subunit B56ε. The novel variant was not observed in the four healthy brothers and was not detected as parental somatic mosaicism. The mutation predicted a change of charge of the mutated amino acid within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation, and thus likely, function. For the first time, we report a potential causal link between the observed variant within the PPP2R5E gene and the symptoms manifested in the subject, spanning specific learning problems and motor coordination disorders potentially associated with myopathy.