title: Homozygous mutation in the eukaryotic translation initiation factor 2alpha phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability.
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.
authors: Children's Hospital of Eastern Ontario Research Institute.
authors: Kristin D
authors: KD
authors: Kernohan
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada H3A 0G1.
authors: Martine
authors: M
authors: Tétreault
authors: Children's Hospital of Eastern Ontario Research Institute.
authors: Urszula
authors: U
authors: Liwak-Muir
authors: Children's Hospital of Eastern Ontario Research Institute, Division of Metabolics and Newborn Screening, Department of Pediatrics.
authors: Michael T
authors: MT
authors: Geraghty
authors: Children's Hospital of Eastern Ontario Research Institute.
authors: Wen
authors: W
authors: Qin
authors: Division of Neurology, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada KIH 8L1.
authors: Sunita
authors: S
authors: Venkateswaran
authors: Department of Radiology and.
authors: Jorge
authors: J
authors: Davila
authors: Children's Hospital of Eastern Ontario Research Institute.
authors: Martin
authors: M
authors: Holcik
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1B1, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada H3A 0G1.
authors: Jacek
authors: J
authors: Majewski
authors: Department of Genetics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
authors: Julie
authors: J
authors: Richer
authors: 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 kboycott@cheo.on.ca.
authors: Kym M
authors: KM
authors: Boycott
mesh_terms: D001665:Binding Sites; D001827:Body Height / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002675:Child, Preschool; D003241:Consanguinity; D004392:Dwarfism / Q000201:enzymology / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D010766:Phosphorylation; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits; D017422:Sequence Analysis, DNA
chemical_list: D018797:Cell Cycle Proteins; D015852:Eukaryotic Initiation Factor-2; D021122:Protein Subunits; D054645:Protein Phosphatase 1