2. Academic Validation
  3. Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability

Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability

  • Hum Mol Genet. 2015 Nov 15;24(22):6293-300. doi: 10.1093/hmg/ddv337.
Kristin D Kernohan 1,  Martine Tétreault 2,  Urszula Liwak-Muir 1,  Michael T Geraghty 3,  Wen Qin 1,  Sunita Venkateswaran 4,  Jorge Davila 5,  Care4Rare Canada Consortium,  Martin Holcik 1,  Jacek Majewski 2,  Julie Richer 6,  Kym M Boycott 7
Affiliations

Affiliations

  • 1 Children's Hospital of Eastern Ontario Research Institute.
  • 2 Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada H3A 0G1.
  • 3 Children's Hospital of Eastern Ontario Research Institute, Division of Metabolics and Newborn Screening, Department of Pediatrics.
  • 4 Division of Neurology, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada KIH 8L1.
  • 5 Department of Radiology and.
  • 6 Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
  • 7 Children's Hospital of Eastern Ontario Research Institute, Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1 [email protected].
PMID: 26307080 DOI: 10.1093/hmg/ddv337
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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