ArticleHuman molecular genetics2015
Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 58 citations in OpenAlex.
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- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Therapeutic Options for Alzheimer's Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm.International journal of molecular sciences · 2026Review
- Metabolic functions for molecular chaperones and stress proteins in microcephaly.Cellular and molecular life sciences : CMLS · 2025Review
- Alzheimer's Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory.International journal of molecular sciences · 2025Review
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- Mapping the Genetic Architecture of the Adaptive Integrated Stress Response inbioRxiv : the preprint server for biology · 2024Article
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- Quintessential Synergy: Concurrent Transient Administration of Integrated Stress Response Inhibitors and BACE1 and/or BACE2 Activators as the Optimal Therapeutic Strategy for Alzheimer's Disease.International journal of molecular sciences · 2024Article
- Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma.Nature communications · 2024Article
- ACH2.0/E, the Consolidated Theory of Conventional and Unconventional Alzheimer's Disease: Origins, Progression, and Therapeutic Strategies.International journal of molecular sciences · 2024Review
- On the Inadequacy of the Current Transgenic Animal Models of Alzheimer's Disease: The Path Forward.International journal of molecular sciences · 2024Article
- Recruitment of trimeric eIF2 by phosphatase non-catalytic subunit PPP1R15B.Molecular cell · 2024Article
- Identifying molecular subgroups of patients with preeclampsia through bioinformatics.Frontiers in cardiovascular medicine · 2024Article
- The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).International journal of molecular sciences · 2023Review
- mir-98-5p regulates gluconeogenesis and lipogenesis by targeting PPP1R15B in hepatocytes.Journal of cell communication and signaling · 2023Article
- Circulating microRNA sequencing revealed miRNome patterns in hematology and oncology patients aiding the prognosis of invasive aspergillosis.Scientific reports · 2022Article
- The role of serine/threonine phosphatases in human development: Evidence from congenital disorders.Frontiers in cell and developmental biology · 2022Review
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.
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