Developmental, Neuroanatomical and Cellular Expression of Genes Causing Dystonia

Dystonia is one of the most common movement disorders, with variants in multiple 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 genes in which variants are dystonia-causing, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed.

We investigated the expression patterns of 44 genes linked with a dystonia phenotype across two bulk and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue.

Dystonia genes were most strongly enriched in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and demonstrated 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 analyses from human frontal cortex, striatum, cerebellum and substantia nigra indicated that dystonia genes are predominantly expressed in neurons (glutamatergic, GABAergic and dopaminergic). Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons and neuron projection.

These analyses provide important insights into the anatomical, developmental, and cellular expression patterns of genes associated with dystonia, potentially guiding the development of disease-relevant models and improving the targeting of future therapeutic interventions.