Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder

Abstract DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, We found 21 patients with loss-of-function variants at DDX53, of whom 19 patients exhibited neurological disorders. Notably, a local patient with a full-length DDX53 deletion mutation had hereditary spastic paraplegia-like (HSP-like) clinical manifestation with lower extremity spasticity, intellectual disability, walking disorder, visual impairment, and lateral ventricular white matter lesions. Bioinformatic analysis revealed that DDX53 was mainly expressed in the cerebellar cortex and may function as a tissue-specific RNA helicase. Transcriptome analysis showed that the expression of multiple brain-associated genes involved in synapse organization, neuron function, and neuromuscular junctions was affected by DDX53 depletion. Moreover, RNA immunoprecipitation sequencing (RIP-seq) analysis showed that DDX53 interacted with 176 genes, and 97 of these genes were associated with the execution of neurofunction, particularly in the regulation of cell projection organization and nervous system development. Collectively, although a more specified cell or animal model is required to fully understand the functional role of DDX53 in the human brain, we report for the first time that DDX53 is required for the maintenance of neuronal function and that loss-of-function mutations in DDX53 may cause HSP due to impaired RNA metabolism in the nervous system.