Furthermore, the ISR key regulators Gadd34, Atf4, Ddit3, and Trib3, which are constitutively activated in VWM patients14,15,27 and 2.5-fold upregulated in homozygous Eif2b5R191H mice (Figure S3E; average fold change across all four transcripts), were only mildly upregulated in homozygous Eif2b4P244L mice (on average, 1.6-fold increase compared to age-matched healthy controls; Figure S3E). Here, DDIT3 is linked to leukoencephalopathy with vanishing white matter.