title: A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
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.
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Baroj
authors.initials: B
authors.lastname: Abdulkarim
authors.affiliation: 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 marc.nicolino@chu-lyon.fr mcnop@ulb.ac.be cecile.julier@inserm.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.affiliation: INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Daures
authors.affiliation: INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Romero
authors.affiliation: INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Philippi
authors.affiliation: INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Senée
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopes
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Cunha
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
authors.forename: Heather P
authors.initials: HP
authors.lastname: Harding
authors.affiliation: Institut de Génomique, Centre National de Génotypage, Commissariat à l'Energie Atomique et aux Energies Alternatives, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Derbois
authors.affiliation: Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Lyon 1 University, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bendelac
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, U.K.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, and National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium Division of Endocrinology, Erasmus Hospital, Brussels, Belgium marc.nicolino@chu-lyon.fr mcnop@ulb.ac.be cecile.julier@inserm.fr.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
authors.affiliation: INSERM UMR-S958, Faculté de Médecine Paris Diderot, Paris, France Université Paris Diderot, Sorbonne Paris Cité, Paris, France marc.nicolino@chu-lyon.fr mcnop@ulb.ac.be cecile.julier@inserm.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Julier
mesh_terms: D000293:Adolescent; D000328:Adult; D003920:Diabetes Mellitus / Q000235:genetics*; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D020125:Mutation, Missense; D054645:Protein Phosphatase 1 / Q000235:genetics*; D013577:Syndrome
chemical_list: D054645:Protein Phosphatase 1