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.

EIF2S3Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO

“…Interestingly, the VWM syndrome pathology is mainly localized to the brain and ovaries, while MEHMO syndrome is more generalized (though the white matter changes are reminiscent of VWM). In contrast, patients with mutations in PPP1R15B share additional symptoms with the EIF2S3 male mutation carriers including diabetes, severe microcephaly, growth retardation, developmental delay, ID, and bone dysplasia [Abdulkarim et al., ; Kernohan et al., ].…”

Neonatal Hypoglycemia, Early-Onset Diabetes and Hypopituitarism Due to the Mutation in EIF2S3 Gene Causing MEHMO Syndrome

“…Earlyonset diabetes and endocrine symptomatology can also be seen in majority of other disorders caused by increased endoplasmic reticulum stress or a dysfunction in the unfolded protein response pathway, i.e. syndromic form of intellectual disability and diabetes caused by mutations in the PPP1R15B (Kernohan et al 2015, Abdulkarim et al 2015 In conclusion, we reported on two patients with MEHMO syndrome with neonatal hypoglycemia followed by early onset diabetes, and hypopituitarism presumably due to dysregulation of protein synthesis and gradual decline of peptide hormone secretion. The genetic analysis of genes involved in protein translation and its regulation needs to be considered in patients with syndromic forms of diabetes and endocrine related syndromes.…”

“…MEHMO syndrome Vol. 67 (OMIM# 300148) is characterized by X-linked intellectual disability, epileptic seizures, hypogonadism, hypogenitalism, microcephaly, and obesity (Leshinsky-Silver et al 2002). Diabetes or endocrine phenotypes have not been included to the main signs of the MEHMO syndrome.…”

Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy

“…Kernohan et al [] and Abdulkarim et al [] described a novel recessive syndrome characterized by severe microcephaly, short stature, delayed myelination, and intellectual disability. The latter family also had pediatric diabetes.…”