PT - JOURNAL ARTICLE AU - Eidhof, Ilse AU - van de Warrenburg, Bart P AU - Schenck, Annette TI - Integrative network and brain expression analysis reveals mechanistic modules in ataxia AID - 10.1136/jmedgenet-2018-105703 DP - 2019 May 01 TA - Journal of Medical Genetics PG - 283--292 VI - 56 IP - 5 4099 - http://jmg.bmj.com/content/56/5/283.short 4100 - http://jmg.bmj.com/content/56/5/283.full SO - J Med Genet2019 May 01; 56 AB - Background Genetic forms of ataxia are a heterogenous group of degenerative diseases of the cerebellum. Many causative genes have been identified. We aimed to systematically investigate these genes to better understand ataxia pathophysiology.Methods A manually curated catalogue of 71 genes involved in disorders with progressive ataxias as a major clinical feature was subjected to an integrated gene ontology, protein network and brain gene expression profiling analysis.Results We found that genes mutated in ataxias operate in networks with significantly enriched protein connectivity, demonstrating coherence on a global level, independent of inheritance mode. Moreover, elevated expression specifically in the cerebellum predisposes to ataxia. Genes expressed in this pattern are significantly over-represented among genes mutated in ataxia and are enriched for ion homeostasis/synaptic functions. The majority of genes mutated in ataxia, however, does not show elevated cerebellar expression that could account for region-specific degeneration. For these, we identified defective cellular stress responses as a major common biological theme, suggesting that the defence pathways against stress are more critical to maintain cerebellar integrity than integrity of other brain regions. Approximately half of the genes mutated in ataxia, mostly part of the stress module, show higher expression at embryonic stages, which argues for a developmental predisposition.Conclusion Genetic defects in ataxia predominantly affect neuronal homeostasis, to which the cerebellum appears to be excessively susceptible. Based on the identified modules, it is conceivable to propose common therapeutic interventions that target deregulated calcium and reactive oxygen species levels, or mechanisms that can decrease the harmful downstream effects of these deleterious insults.