De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

Abstract

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A-and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Ca subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(d) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

“… 36 , 37 In 2015, PP2A dysfunction was reported as a new cause of syndromic intellectual disability and (neuro)developmental delay, involving de novo loss-of-function pathogenic variants in PPP2R1A and PPP2R5D , 4 and likely also in PPP2R5C and PPP2R5B , although the latter has not yet been functionally confirmed. 5 Later, the set of affected genes was extended to PPP2CA , 6 and the overlapping syndromes, all characterized by severe PP2A dysfunction, were proposed to be called “PP2A-related neurodevelopmental disorders.” Here, we significantly expand the spectrum of PPP2R1A variants and phenotypes through analysis of 30 additional patients. While all previously reported PPP2R1A -affected cases represented individuals with severe ID, often associated with epilepsy and microcephaly, more diversity is seen in the current cohort, with several cases being phenotypically milder, and at least one without ID but with only learning problems and autistic features.…”

“…Among the new causes discovered are de novo, often recurrent, pathogenic variants in subunits of the protein phosphatase type 2A (PP2A), the major serine/threonine phosphatase in the human body. 1 – 6 Since PP2A counterbalances Ser/Thr-specific protein kinase activity, this phosphatase plays an essential regulatory role in cellular signaling and physiology. 7 , 8 PP2A phosphatases are holoenzymes, comprising three subunits: a catalytic C, a scaffolding A and a regulatory B-type subunit, encoded by 19 different genes in total (2 for C, 2 for A, and 15 for B subunits).…”

“…Functional characterization also revealed losses of function, consistent with decreased PP2A-B56(δ) functionalities in most cases—either by a dominant-negative mechanism, or by haploinsufficiency. 6 Finally, a non-sense variant in BOD1 (encoding a cellular inhibitor of PP2A-B56 complexes) was reported to cosegregate with ID in a consanguineous family, 18 and a familial reciprocal translocation (4;6)(p16.1;q22) disrupting PPP2R2C (encoding the PP2A-B55γ subunit) was associated with mild ID, epilepsy, and behavioral problems. 19 …”

PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans

“…Heterozygous de novo missense mutations in PP2A regulatory subunit B family genes, PPP2R5B, PPP2R5C and PPP2R5D, have recently been described in individuals with overgrowth and intellectual disability (42). De novo mutations affecting the catalytic Cα subunit of PP2A (PPP2CA) were identified to cause a syndromic intellectual disability and developmental delay (43). However, no homozygous mutations was identified in those conditions.…”

MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor

“… 24 , 25 Mutations in PPP2CA cause neurodevelopmental disorder and language delay with or without structural brain abnormalities, in which facial dysmorphias are reported. 26 Variants in MAP3K5, with which MAP3K6 interacts and forms dimers, affect the risk for schizophrenia. 27 Mutations in the kinases of the parallel MAPK-Ras pathway cause the neurodevelopmental syndromes Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous syndrome.…”