A novel variant inADPRSdisrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure

Abstract

PurposeADP-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 theADPRSgene (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).MethodsGenetic 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.ResultsThe ARH3H182Rvariant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3H182Radditionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3H182Rresulted in accumulation of mono-ADP ribosylated species in cells.ConclusionsThe 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.