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-TRNAwith 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 a subunit of eIF2 (eIF2a); phosphorylated eIF2a attenuates protein translation. Here,we report a consanguineous familywith 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.1972GA; P.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a proteinwhich functions with the PPP1C phosphatase to maintain dephosphorylated eIF2a in unstressed cells. The p.R658C PPP1R15Bmutation is locatedwithin the PPP1C binding site.We showthat patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2a 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.