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

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    URI
    http://hdl.handle.net/11287/618123
    Author
    Abdulkarim, B.
    Nicolino, M.
    Igoillo-Esteve, M.
    Daures, M.
    Romero, S.
    Philippi, A.
    Senée, V.
    Lopes, M.
    Cunha, D. A.
    Harding, H. P.
    Derbois, C.
    Bendelac, N.
    Hattersley, Andrew T.
    Eizirik, D. L.
    Ron, D.
    Cnop, M.
    Julier, C.
    Date
    2015-11
    Journal
    Diabetes
    Type
    Journal Article
    Case Report
    Research Support, Non-U.S. Gov't
    Publisher
    American Diabetes Association
    DOI
    10.2337/db15-0477
    Rights
    Archived with thanks to Diabetes
    Metadata
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    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.
    Citation
    A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly. 2015, 64 (11):3951-62 Diabetes
    Publisher URL
    http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26159176
    Note
    This article is freely available via the publisher's site - click on the 'Additional Link' above to access the full text.
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    • 2015 RD&E publications
    • Diabetes/Endocrine Services

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