De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Abstract

Permanent neonatal diabetes mellitus (PNDM) is caused by reduced b-cell number or impaired b-cell function. Understanding of the genetic basis of this disorder highlights fundamental b-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex a subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for b-cells and highlight EIF2B1's fundamental role within this pathway.

2. Classification and Diagnosis of Diabetes:Standards of Medical Care in Diabetes—2021

“…Additionally, diagnosis can lead to identification of other affected family members. Genetic screening is increasingly available and costeffective (138,140).…”

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

“…Previous studies have shown that neonatal diabetes is most likely caused by a mutation in a single gene, rather than being autoimmune type 1 diabetes (1,2). To date, 30 genetic causes have been described, which account for 82% of cases (3)(4)(5)(6)(7)(8)(9). Additional clinical features are often present in patients with neonatal diabetes, with 18% of them having neurological symptoms (3).…”

“…One of the pathways known to be crucial for the function of both β and brain cells is the endoplasmic reticulum (ER) stress response. Pathogenic variants in 8 genes known to be involved in regulating the ER stress response have been found to cause diabetes (ranging from neonatal to adolescent/adult-onset diabetes), often associated with neurological features ( 6 , 16 ). The ER stress response is an adaptive pathway that is triggered when there is an imbalance in the ability of the ER to fold proteins and the cellular protein folding demand, leading to accumulation of unfolded or misfolded proteins in the ER.…”

Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population

“…This complex is crucial for initiating the translation of mRNAs into peptides and therefore regulates the translation rate in the context of several different stress conditions ( Rabouw et al, 2019 ; Marintchev and Ito, 2020 ). Variants in this gene have been associated with inappropriate insulin secretion from pancreatic β-cells ( Bursle et al, 2019 ) and mutations in other subunits, which affect eIF2 signaling, have been associated with early onset diabetes ( De Franco et al, 2020 ). Moreover, studies in animal models have connected eIF2 signaling to heart inflammation cardiac hypertrophy ( Zhang et al, 2020 ).…”