Characterizing the Structural and Physiological Effects of IMPDH2 Mutations Associated with Neurodevelopmental Disorders

Abstract

Inosine-5'-monophosphate dehydrogenase (IMPDH) catalyzes the first committed step of de novo guanine nucleotide biosynthesis, converting IMP to XMP. To control this important metabolic branch point between adenine and guanine nucleotide synthesis, IMPDH is highly regulated, including through assembly into filaments. There are two isoforms of IMPDH in humans, but IMPDH2 is specifically essential for development and is upregulated during proliferation. Mutations in IMPDH2 have been identified in patients with neurodevelopmental disorders exhibiting a range of neurological symptoms, including dystonia. Here, we show with in vitro enzyme assays, negative stain electron microscopy, and high-resolution structures determined by cryo-EM, how each mutation affects the structure, activity, and allosteric regulation of IMPDH2 filaments and octamers. We also develop Xenopus tropicalis as a model to study the effects of one variant, the in-frame deletion of serine 160, on metabolism, neuromuscular development, and IMPDH filament formation in a vertebrate system. This work establishes a model for studying the mechanisms of disease that arise from IMPDH2 dysregulation.