PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

Abstract

Protein Phosphatase 2 Regulatory Subunit B′ Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer’s disease, and Parkinson’s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A–PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A–PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A–PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson’s disease, Alzheimer’s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.

A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

“…Variants in PPP2R5D are associated with mild to severe global developmental delay, hypotonia, ID, ASD, and behavioral abnormalities. Among these, pronounced hypotonia with delay in gross motor skills is the most frequently occurring symptom of PPP2R5D-related neurodevelopmental disorder [ 6 – 9 ]. Ever since PPP2R5D-related NDD was identified by Del-Mazo in 1996, more than 100 individuals with PPP2R5D-related NDD have been described.…”

PPP2R5D Genetic Mutations and Early‐Onset Parkinsonism

“…2 Mutations in this gene have been associated with heterogeneous neurodevelopmental disorders, including intellectual disability, autism-spectrum disorder (ASD), infantile hypotonia, and epilepsy. 3 We recently identified a different missense variant (p. E250K) in the PPP2R5D gene in a patient with juvenile-onset parkinsonism. Our patient had a history of delayed early developmental milestones and macrocephaly.…”

“…In addition, very few genetic causes of syndromes of intellectual disability associated with early onset parkinsonism have been reported other than PPP2R5D. 1,2 According to the American College of Medical Genetics and Genomics criteria, 3 this variant would be classified as likely pathogenic (Criteria PS2 + PM2 + PP2 + PP3 + PP4).…”

PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases

“…Whole-exome sequencing studies have assisted in the recognition of this disorder in 69 patients with 13 different genetic variations. 18,19 These have been mostly reported from the America, China, and European countries. 8,10,11 The index case is the first report from India.…”