Developmental, neuroanatomical and cellular expression of genes causing dystonia

Abstract

ObjectiveDystonia is one of the most common forms of movement disorder with >50 genes identified as causative. However, an understanding of which developmental stages, brain regions and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of dystonia-causing genes, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed. MethodsWe investigated the expression patterns of 44 dystonia-causing genes across two bulk- and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue. ResultsDystonia genes were most strongly enriched in those with higher expression in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and for higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing data analyses from human frontal cortex, striatum and cerebellum indicated that dystonia genes are predominantly expressed in neurons (both glutamatergic and GABAergic), rather than glia. Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons, presynapse and neuron projection. InterpretationThese analyses provide important insights into the anatomical, developmental and cellular expression patterns of dystonia-causing genes, potentially guiding the development of disease-relevant models and improving the timing and targeting of future therapeutic interventions.