De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction
De Franco, E; Caswell, R; Johnson, M; et al.Wakeling, M; Zung, S; Dũng, VC; Ngọc, CTB; Goonetilleke, R; Jury, MV; ElKhateeb, M; Ellard, S; Flanagan, SE; Ron, D; Hattersley, AT
Date: 27 December 2019
Journal
Diabetes
Publisher
American Diabetes Association
Publisher DOI
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Abstract
Permanent neonatal diabetes is caused by reduced β-cell number or impaired β-cell function.
Understanding the genetic basis of this disorder highlights fundamental β-cell mechanisms.
We performed trio genome sequencing for 44 permanent neonatal diabetes patients and their
unaffected parents to identify causative de novo variants. ...
Permanent neonatal diabetes is caused by reduced β-cell number or impaired β-cell function.
Understanding the genetic basis of this disorder highlights fundamental β-cell mechanisms.
We performed trio genome sequencing for 44 permanent neonatal diabetes patients 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 α subunit) was the only gene with novel de novo variants (all
missense) in at least three patients. Replication studies identified 2 further patients with de novo
EIF2B1 variants. In addition to diabetes, 4/5 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 β-cells and highlight
EIF2B1’s fundamental role within this pathway.
Institute of Biomedical & Clinical Science
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