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

  • Diabetes. 2015 Nov;64(11):3951-62. doi: 10.2337/db15-0477.
Baroj Abdulkarim  1 ,  Marc Nicolino  2 ,  Mariana Igoillo-Esteve  1 ,  Mathilde Daures  3 ,  Sophie Romero  3 ,  Anne Philippi  3 ,  Valérie Senée  3 ,  Miguel Lopes  1 ,  Daniel A Cunha  1 ,  Heather P Harding  4 ,  Céline Derbois  5 ,  Nathalie Bendelac  6 ,  Andrew T Hattersley  7 ,  Décio L Eizirik  1 ,  David Ron  4 ,  Miriam Cnop  8 ,  Cécile Julier  9
Affiliations
  • 1. ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
  • 2. Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Lyon 1 University, Lyon, France INSERM U870, Lyon, France INSERM CIC201, Lyon, France [email protected] [email protected] [email protected].
  • 3. INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
  • 4. Cambridge Institute for Medical Research, University of Cambridge, and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
  • 5. Institut de Génomique, Centre National de Génotypage, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France.
  • 6. Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Lyon 1 University, Lyon, France.
  • 7. University of Exeter Medical School, University of Exeter, Exeter, U.K.
  • 8. ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium Division of Endocrinology, Erasmus Hospital, Brussels, Belgium [email protected] [email protected] [email protected].
  • 9. INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France [email protected] [email protected] [email protected].
PMID: 26159176 DOI: 10.2337/db15-0477
Abstract

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic β-cell failure and diabetes. Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2α phosphorylation [CReP]) encoding the regulatory subunit of an eIF2α-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 eIF2α dephosphorylation and results in β-cell Apoptosis. Our findings support the concept that dysregulated eIF2α phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the Phosphatase (PPP1R15B), is deleterious to β-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.