Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure

Abstract

Inosine 5' monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report identification of two additional affected individuals with missense variants in IMPDH2 and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.

Nuclear cytoophidia assembly represses transcriptional activity to control skeletal development and homeostasis

“…However, given the evolutionary conservation of Impdh2, we do not investigate whether Impdh2 also functions as a transcription factor in other tissues or species. In addition, although we demonstrated that nuclear filamentation inhibits the transcriptional activity of Impdh2 during limb formation and bone resorption, evidence has shown that IMPDH2 are associated with neurodevelopmental disorders (Lake et al, 2016, O'Neill et al, 2023 and inflammation-relevant diseases (Liao et al, 2017). This evidence does not rule out a possible role for the nuclear Impdh2-assembled cytoophidia function in these pathological processes.…”