PPP2R5D – Hogue-Janssens syndrome 1

Houge-Janssens syndrome 1 is an early-childhood onset neurodevelopmental disorder caused by heterozygous missense and truncating variants in PPP2R5D, which encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A). A large cohort of 76 individuals, including 68 de novo cases, delineates a core phenotype of intellectual disability, hypotonia, macrocephaly, autism spectrum disorder and seizures (PMID:36216457).

Inheritance is autosomal dominant, with de novo origin in most probands. Segregation in familial cases includes four affected siblings with a dominantly inherited variant and two affected relatives (one non-penetrant) in a three‐generation pedigree (PMID:36216457; PMID:36403339).

Genetic evidence comprises at least 69 unrelated probands with pathogenic variants—13 distinct missense substitutions, one recurrent hotspot at Glu198 (c.592G>A (p.Glu198Lys)) accounting for ~40% of cases, and rare frameshift/nonsense alleles (PMID:37572851; PMID:36216457).

Functional studies demonstrate a dominant-negative mechanism. CRISPR-engineered E420K variant cells exhibit constitutive AKT-mTOR activation, increased cell size, and rescue by rapamycin (PMID:33482199). Phosphoproteomic profiling of E198K and E420K lines reveals RPS6 hyperphosphorylation and mTORC1 dependency reversed by rapamycin or p70S6K inhibition (PMID:37572851).

Structural cryo-EM of the PP2A-B56δ holoenzyme uncovers autoinhibitory disordered arms; ID-associated mutations perturb this interface, enhance holoenzyme activity and increase mitotic error rates, supporting a gain-of-function/dominant-negative model (PMID:38150499).

Integration of genetic and experimental data supports a Strong gene-disease association: over 69 unrelated probands with de novo variants, familial segregation (6 affected relatives), and concordant functional evidence of aberrant PI3K/AKT/mTOR signaling. Additional evidence exceeds scoring caps. Key take-home: PPP2R5D molecular testing informs diagnosis of Hogue-Janssens syndrome 1 and highlights mTOR pathway inhibition as a potential therapeutic strategy.

References

• Pediatric Reports • 2024 • PPP2R5D-Related Neurodevelopmental Disorder and Multiple Haemangiomas: A Novel Phenotypic Trait? PMID:39728742
• Journal of Medical Genetics • 2023 • Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype-phenotype analysis. PMID:36216457
• Clinical Neurology and Neurosurgery • 2022 • A novel nonsense mutation in PPP2R5D is associated with neurodevelopmental disorders and shows incomplete penetrance in a Chinese pedigree. PMID:36403339
• The Journal of Biological Chemistry • 2021 • A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth. PMID:33482199
• The Journal of Biological Chemistry • 2023 • Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades. PMID:37572851
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations PMID:38150499

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