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

被引：77

作者：

Abdulkarim, Baroj ^{[1
]}

Nicolino, Marc ^{[2
,3
,4
]}

Igoillo-Esteve, Mariana ^{[1
]}

Daures, Mathilde ^{[5
,6
]}

Romero, Sophie ^{[5
,6
]}

Philippi, Anne ^{[5
,6
]}

Senee, Valerie ^{[5
,6
]}

Lopes, Miguel ^{[1
]}

Cunha, Daniel A. ^{[1
]}

Harding, Heather P. ^{[7
,8
]}

Derbois, Celine ^{[9
]}

Bendelac, Nathalie ^{[2
]}

Hattersley, Andrew T. ^{[10
]}

Eizirik, Decio L. ^{[1
]}

Ron, David ^{[7
,8
]}

Cnop, Miriam ^{[1
,11
]}

Julier, Cecile ^{[5
,6
]}

机构：

[1] Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium

[2] Univ Lyon 1, Hosp Civils Lyon, Div Pediat Endocrinol, Hop Femme Mere Enfant, F-69365 Lyon, France

[3] INSERM, U870, F-69008 Lyon, France

[4] INSERM, CIC201, F-69008 Lyon, France

[5] INSERM, UMR S958, Fac Med Paris Diderot, Paris, France

[6] Univ Paris Diderot, Sorbonne Paris Cite, Paris, France

[7] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[8] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England

[9] Ctr Natl Genotypage, Inst Genom, Commissariat Energie Atom & Energies Alternat, Evry, France

[10] Univ Exeter, Univ Exeter Med Sch, Exeter, Devon, England

[11] Erasmus Hosp, Div Endocrinol, Brussels, Belgium

来源：

DIABETES | 2015年 / 64卷 / 11期

基金：

英国惠康基金;

关键词：

ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; BETA-CELL DYSFUNCTION; FREE FATTY-ACIDS; FACTOR-KAPPA-B; EIF2-ALPHA DEPHOSPHORYLATION; TRANSLATIONAL CONTROL; INDUCED APOPTOSIS; INITIATION; INHIBITION;

D O I：

10.2337/db15-0477

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) 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 eIF2 alpha phosphorylation [CReP]) encoding the regulatory subunit of an eIF2 alpha-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 eIF2 alpha dephosphorylation and results in beta-cell apoptosis. Our findings support the concept that dysregulated eIF2 alpha 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.

引用

页码：3951 / 3962

页数：12

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