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Here, we report the first homozygous mutation in the PPP1R15B gene (also known as constitutive repressor of eIF2\u03b1 phosphorylation [CReP]) encoding the regulatory subunit of an eIF2\u03b1-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\u03b1 dephosphorylation and results in \u03b2-cell apoptosis. Our findings support the concept that dysregulated eIF2\u03b1 phosphorylation, whether decreased by mutation of the kinase (EIF2AK3) in Wolcott-Rallison syndrome or increased by mutation of the phosphatase (PPP1R15B), is deleterious to \u03b2-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.<\/jats:p>","DOI":"10.2337\/db15-0477","type":"journal-article","created":{"date-parts":[[2015,7,10]],"date-time":"2015-07-10T02:35:14Z","timestamp":1436495714000},"page":"3951-3962","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":101,"title":["A Missense Mutation in <i>PPP1R15B<\/i> Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly"],"prefix":"10.2337","volume":"64","author":[{"given":"Baroj","family":"Abdulkarim","sequence":"first","affiliation":[{"name":"ULB Center for Diabetes Research, Universit\u00e9 Libre de Bruxelles, Brussels, 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