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Article Dans Une Revue Diabetes Année : 2015

A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly

B. Abdulkarim
  • Fonction : Auteur
M. Igoillo-Esteve
  • Fonction : Auteur
M. Daures
  • Fonction : Auteur
S. Romero
  • Fonction : Auteur
A. Philippi
  • Fonction : Auteur
V. Senee
  • Fonction : Auteur
M. Lopes
  • Fonction : Auteur
D. A. Cunha
  • Fonction : Auteur
H. P. Harding
  • Fonction : Auteur
C. Derbois
  • Fonction : Auteur
N. Bendelac
  • Fonction : Auteur
A. T. Hattersley
  • Fonction : Auteur
D. L. Eizirik
  • Fonction : Auteur
D. Ron
  • Fonction : Auteur
M. Cnop
  • Fonction : Auteur
C. Julier
  • Fonction : Auteur

Résumé

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) are associated with pancreatic beta-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2alpha phosphorylation [CReP]) encoding the regulatory subunit of an eIF2alpha-specific phosphatase in two siblings affected by a novel syndrome of diabetes of youth with short stature, intellectual disability, and microcephaly. The R658C mutation in PPP1R15B affects a conserved amino acid within the domain important for protein phosphatase 1 (PP1) binding. The R658C mutation decreases PP1 binding and eIF2alpha dephosphorylation and results in beta-cell apoptosis. Our findings support the concept that dysregulated eIF2alpha phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to beta-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.

Dates et versions

hal-01850506 , version 1 (27-07-2018)

Identifiants

Citer

B. Abdulkarim, Marc Nicolino, M. Igoillo-Esteve, M. Daures, S. Romero, et al.. A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. Diabetes, 2015, 64 (11), pp.3951-62. ⟨10.2337/db15-0477⟩. ⟨hal-01850506⟩
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