The adaptive nature of the ISR during embryogenesis is exemplified by Wolcott-Rallison syndrome, a human disorder in which homozygous loss-of-function mutations in the gene encoding PERK (EIF2AK3) result in neonatal diabetes (15); this phenotype is mirrored in Eif2ak3–/– mice (16). This evidence concerns the gene EIF2AK3 and Wolcott-Rallison syndrome.