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.

OBJECTIVE: Genes responsible for monogenic forms of diabetes have proven very valuable for understanding key mechanisms involved in β-cell development and function. Genetic study of selected families is a powerful strategy to identify such genes. We studied a consanguineous family with two first cousins affected by neonatal diabetes; their four parents had a common ancestor, suggestive of a fully penetrant recessive mutation. RESEARCH DESIGN AND METHODS: We performed genetic studies of the family, detailed clinical and biochemical investigations of the patients and the four parents, and biochemical and functional studies of the new mutation. RESULTS: We found a novel mutation in the pancreatic and duodenal homeobox 1 gene (PDX1, IPF1) in the two patients, which segregated with diabetes in the homozygous state. The mutation resulted in an E178G substitution in the PDX1 homeodomain. In contrast to other reported PDX1 mutations leading to neonatal diabetes and pancreas agenesis, homozygosity for the E178G mutation was not associated with clinical signs of exocrine pancreas insufficiency. Further, the four heterozygous parents were not diabetic and displayed normal glucose tolerance. Biochemical studies, however, revealed subclinical exocrine pancreas insufficiency in the patients and slightly reduced insulin secretion in the heterozygous parents. The E178G mutation resulted in reduced Pdx1 transactivation despite normal nuclear localization, expression level, and chromatin occupancy. CONCLUSIONS: This study broadens the clinical spectrum of PDX1 mutations and justifies screening of this gene in neonatal diabetic patients even in the absence of exocrine pancreas manifestations.

Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell–derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress–induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.

Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early-infancy-onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3-W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype.