A novel spinocerebellar ataxia characterized by exonic CAG repeat expansion in the THAP11 gene

Objectives: Spinocerebellar ataxias (SCAs) are a group of inherited, heterogeneous neurodegenerative disorders that mainly affect the cerebellum. To date, over 40 distinct pathogenic genes have been identified to be associated with SCAs. Here, we diagnosed a Chinese SCA pedigree and identified CAG repeat expansions in exon 1 of THAP11. Methods: CAG repeat expansions in THAP11 gene were identified in this SCA family by using a comprehensive strategy combining long-read whole-genome sequencing, capillary electrophoresis fragment analysis, and direct DNA sequencing. The pathogenesis of SCA caused by CAG repeat expansions in THAP11 gene was studied in skin fibroblasts of patients, and mutant HEK293 and neuro-2a. Results: Normal THAP11 contained 28/29 CAG repeats while affected patients had (CAG)45 to (CAG)100 repeat expansions. Intracellular aggregates caused by mutant THAP11-polyglutamine proteins with CAG repeat expansions were observed in cultured skin fibroblasts from affected patients, as well as mutant HEK293 and neuro-2a. RNA sequencing indicated that the dysregulations of cell differentiation and DNA-binding might involve in the pathogenic mechanisms. Furthermore, SQSTM1/p62, phospho-ubiquitin and c-Myc were co-localized with intracellular aggregates in skin fibroblasts of SCA patients. Meanwhile, the protein levels of THAP11, SQSTM1/p62 and c-Myc were increased. Conclusion: This study confirmed a novel SCA characterized by exonic CAG repeat expansion in the THAP11 gene, and provided information for possible pathogenesis of SCA due to mutant THAP11.
Keywords: spinocerebellar ataxia; THAP11; polyglutamine disease; intracellular aggregate; long-read whole-genome sequencing