ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 2.7 | DOI: 10.1530/ey.17.2.7

Neonatal Diabetes Mellitus

2.7. De novo mutations in EIF2B1 affecting eif2 signaling cause neonatal/early-onset diabetes and transient hepatic dysfunction

De Franco E, Caswell R, Johnson MB, Wakeling MN, Zung A, Dung VC, Bích Ngoc CT, Goonetilleke R, Vivanco Jury M, El-Khateeb M, Ellard S, Flanagan SE, Ron D & Hattersley AT


To read the full abstract: Diabetes. 2020 Mar;69(3):477–483. doi: 10.2337/db19-1029. Epub 2019 Dec 27. PMID: 31882561

Endoplasmic recticulum (ER) stress plays an important role in the etiology of several forms of diabetes mellitus. There is evidence that ER stress plays a role in both type 1 and type 2 diabetes. More importantly molecular defects in the ER stress pathway are linked to monogenic and syndromic forms of diabetes mellitus. ER stress is defined as an imbalance between the protein folding capacity of the cell and the functional demand that is placed on it. Any imbalance will lead to the accumulation of unfolded or misfolded proteins in the ER lumen. In order to restore ER homeostasis, cells trigger the ER stress response, also known as the unfolded protein response (UPR). The proteins synthesized in the ER comprise all secreted and membrane expressed proteins and any mutation leading to misfolding of these proteins in the ER can theoretically cause ER stress and beta-cell damage and diabetes.

This paper describes a novel disorder of permanent neonatal/early onset diabetes with transient hepatic dysfunction due to mutations in the gene EIF2B1. This gene encodes for the alpha subunit of a complex in the ER which regulates and initiates the ER stress response. The phenotype of the five patients described overlaps with another disorder linked to ER stress called Wolcott–Rallison syndrome (WRS) and is in the same pathway as the EIF2B1. However, the clinical spectrum of WRS is more severe with most patients dying from hepatic dysfunction. All of the mutations in the five patients were de-novo and in heterozygote state. In-silico studies showed that these mutations impaired phosphorylation of the alpha subunit. Interestingly, homozygous mutations in EIF2B1 lead to a severe fatal neurological disorder characterized by leukoencephalopathy with vanishing white matter (VWM). Only one of the five patients described had a mild learning disability. These observations expand our knowledge about the ER stress pathways and suggest that genetic testing for EIF2B1 should be undertaken in any patient with early onset diabetes and hepatic dysfunction, even if only transient.

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