A Missense Mutation in PPP1R15B Causes a Syndrome Including Diabetes, Short Stature, and Microcephaly.
Diabetes
; 64(11): 3951-62, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26159176
ABSTRACT
Dysregulated endoplasmic reticulum stress and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) are associated with pancreatic ß-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 ß-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 ß-cells and other secretory tissues, resulting in diabetes associated with multisystem abnormalities.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Mutación Missense
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Diabetes Mellitus
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Proteína Fosfatasa 1
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Trastornos del Crecimiento
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Microcefalia
Tipo de estudio:
Etiology_studies
Límite:
Adolescent
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Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Diabetes
Año:
2015
Tipo del documento:
Article
País de afiliación:
Bélgica