DPH1 (diphthamide biosynthesis 1) catalyzes the first committed step of diphthamide biosynthesis, a post-translational modification of a histidine residue on elongation factor 2 (EEF2) 1. DPH1 and DPH2 work together to transfer a 3-amino-3-carboxypropyl group from S-adenosyl-L-methionine to this critical histidine, with assistance from DPH3 and NADH-dependent reductase components 1. Diphthamide modification is essential for proper translational fidelity and protein synthesis elongation in eukaryotic ribosomes 2. Autosomal-recessive DPH1 mutations cause diphthamide deficiency syndrome, characterized by intellectual disability, developmental delay, short stature, dysmorphic facial features, sparse hair, seizures, and craniofacial abnormalities 34. This phenotype results from impaired EEF2 function and compromised protein synthesis 4. Variant analysis has identified multiple loss-of-function alleles that reduce enzyme activity and catalytic efficiency 5. Notably, DPH1 downregulation in myeloid malignancies confers resistance to tagraxofusp (a diphtheria toxin-based therapeutic), though azacitidine can restore DPH1 expression and drug sensitivity 6. Additionally, DPH1 variants are implicated as risk factors in bipolar disorder based on fine-mapping analyses 7.