DPH5 encodes a cytosolic S-adenosyl-L-methionine-dependent methyltransferase that catalyzes four successive methylation reactions on modified histidine residues in translation elongation factor 2 (eEF2), forming diphthine methyl ester as an intermediate in diphthamide biosynthesis 1. Diphthamide is a post-translational modification essential for messenger RNA translation and ribosomal protein synthesis 1. DPH5 functions as part of a seven-protein system (DPH1-7) required for complete diphthamide synthesis, with DPH5 catalyzing the second biosynthetic step 2. Loss-of-function DPH5 variants cause DPH5-related diphthamide-deficiency syndrome, manifesting as embryonic lethality or profound neurodevelopmental disorders with multisystem abnormalities including craniofacial dysmorphology, developmental delay, intellectual disability, and growth impairment 13. Homozygous DPH5 mutations are embryonically lethal in mice, while hypomorphic variants produce milder phenotypes with variable severity 3. Recent evidence suggests DPH5 dysregulation may be implicated in intervertebral disc degeneration, with decreased DPH5 expression observed in degenerative nucleus pulposus tissue 4. Functionally compromised DPH5 variants can affect cellular sensitivity to ADP-ribosylating toxins and immunotoxin-based therapies that target diphthamide-containing eEF2 5.