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PPP3CA encodes the catalytic A subunit of calcineurin, a calcium/calmodulin-dependent serine-threonine phosphatase crucial for neuronal signaling. Pathogenic PPP3CA variants present with two distinct phenotypes: gain-of-function mutations in the autoinhibitory domain cause a multiple congenital anomaly disorder, while loss-of-function variants underlie infantile or early childhood onset epileptic encephalopathy. The latter, designated developmental and epileptic encephalopathy 91, manifests with refractory seizures, psychomotor delay, and global developmental impairment. Mouse models with calcineurin Aα deficiency recapitulate aspects of the human neurodevelopmental phenotype, reinforcing the functional role of PPP3CA in cortical maturation. International consensus classifies this association as autosomal dominant based on recurrent de novo events. Here, we summarize genetic and experimental evidence linking PPP3CA loss-of-function to developmental and epileptic encephalopathy 91.
Genetic evidence comprises multiple independent cohorts reporting de novo PPP3CA variants in unrelated patients. Twelve subjects with de novo missense variants in the catalytic domain were described, exhibiting early-onset seizures and dysmorphic features (PMID:30254215). Five additional patients with truncating frameshift variants clustered within a 26–amino acid region of the regulatory domain displayed more severe early refractory epilepsy (PMID:33963760). Two patients harboring a frameshift and a splice-site variant expanded the phenotypic spectrum to include moderate developmental delay in one individual (PMID:39707491). Single case reports further detail individual instances of infantile-onset epileptic encephalopathy with frameshift variants (PMID:32593294, PMID:36158964). A representative Chinese patient was found to carry a frameshift variant c.1283insC (p.Thr429AsnfsTer22), confirming the critical role of PPP3CA loss-of-function in disease (PMID:32593294).
No evidence of vertical transmission has been documented, consistent with a de novo dominant mechanism. Variant spectrum includes missense alterations in the catalytic core, truncating frameshift variants in the regulatory domain, and rare splice-site changes. Recurrent missense substitutions at Glu282 exemplify mutational hotspots in the catalytic domain. Carrier frequency data are not available due to the rarity of de novo events. Segregation analysis is limited by absence of familial recurrence and underscores de novo origin. These findings collectively satisfy genetic criteria for a strong gene-disease association.
Functional studies provide moderate evidence of pathogenicity. In patient-derived lymphocytes and neuronal models, truncating alleles yield markedly reduced protein expression despite normal mRNA abundance, indicating post-transcriptional degradation (PMID:30254215). In vitro phosphatase assays demonstrate constitutive calcineurin activation for regulatory domain truncating variants, supporting a loss of auto-inhibitory control (PMID:30254215). Animal data from calcineurin Aα knockout mice recapitulate cognitive and motor deficits, lending in vivo support for haploinsufficiency. Splice variants altering isoform distribution trigger endoplasmic reticulum stress and upregulation of the unfolded protein response in patient cells (PMID:39707491). These functional concordances align with the observed human phenotype of early refractory seizures and developmental delay.
Mechanistically, pathogenic PPP3CA alleles result in loss-of-function via haploinsufficiency or dominant-negative effects of truncated proteins. Truncating variants in the regulatory domain abolish autoinhibitory interactions, whereas catalytic domain missense mutations disrupt phosphatase activity. Both variant classes impair neuronal calcium signaling and synaptic plasticity, culminating in epileptic and developmental manifestations. No studies to date refute this association or propose alternative molecular etiologies for PPP3CA-related encephalopathy. Thus, the weight of evidence supports a haploinsufficiency mechanism underpinning developmental and epileptic encephalopathy 91. Further animal model characterization may delineate genotype-phenotype correlations and treatment responses.
Current evidence robustly supports a ClinGen classification of Strong for the PPP3CA–developmental and epileptic encephalopathy 91 association. Genetic testing for PPP3CA variants enables definitive diagnosis in infants with refractory seizures and global developmental delay. Integration of variant data into diagnostic panels and trio exome sequencing pipelines is recommended for early detection. Future studies should explore targeted calcineurin modulators as potential therapeutic avenues. In summary, heterozygous de novo PPP3CA loss-of-function variants are a clinically actionable cause of severe infantile epileptic encephalopathy. Key Take-home: PPP3CA screening informs diagnosis and guides research into precision therapies for developmental and epileptic encephalopathy 91.
Gene–Disease AssociationStrongMultiple independent de novo PPP3CA LoF and missense variants reported in >20 unrelated individuals with consistent phenotype and functional corroboration Genetic EvidenceStrongDe novo LoF and missense variants in at least five independent cohorts encompassing 21 probands, including 12 missense and 9 truncating variants Functional EvidenceModerateCellular assays reveal constitutive enzyme activation, reduced protein expression, aberrant splicing, and unfolded protein response consistent with loss-of-function mechanism |