Abstract
PURPOSE: ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS). METHODS: Genetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change. RESULTS: The ARH3 (H182R) variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3 (H182R) additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3 (H182R) resulted in accumulation of mono-ADP ribosylated species in cells. CONCLUSIONS: The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.