Neurodegenerative disorders associated with heterozygous dominant variants in KPNA3 and KPNA4

• Applicant: Professor Dr. Stefan Kindler
• Subject Area: Human Genetics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566606007

Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disorder characterized by weakness and spasticity of the lower limbs due to progressive degeneration of upper motor neurons that form corticospinal tracts. To date, variants in more than 80 different genes have been associated with HSP. Recently, we identified distinct heterozygous variants of KPNA3 that are associated with HSP. KPNA3 encodes karyopherin subunit alpha 3 (KPNA3), a nuclear transport receptor that promotes the passage of nucleophilic proteins through the nuclear pore complex into the nuclear matrix. Thus, our study for the first time implicates impaired nucleocytoplasmic protein trafficking as a possible pathomechanism for HSP. Functional analyses showed that all identified KPNA3 variants are impaired in cellular abundance, subcellular localization and/or cargo protein recognition. Since then, we have identified several new heterozygous KPNA3 variants that cause early-onset HSP, ataxia or other neurodevelopmental phenotypes. We have also found six different heterozygous de novo variants in KPNA4, a closely related paralogue of KPNA3, each of which represents the most convincing pathogenic genetic change in individuals with developmental delay in various domains. Affected individuals also present with HSP, ataxia, intellectual disability and/or various neuropsychiatric symptoms. Taken together, our findings show that pathogenic heterozygous variants in both KPNA3 and KPNA4 can result in overlapping disease phenotypes, mostly spasticity-ataxia phenotype (SAP) spectrum disorders, which may result from deficits in common cellular pathways and thus lead to related pathomechanisms. The main goal of this proposal is to better understand the molecular actions and cellular functions of both KPNA3 and KPNA4 to determine similarities and differences. In addition, we aim to identify how different pathogenic variants in KPNA3 and KPNA4 may lead to the pathogenesis of SAP spectrum disorders and other neurodevelopmental conditions. Therefore, we will use various assays to determine the protein-protein interactome of both proteins, their molecular structure, intra- and intermolecular interaction pattern, cellular abundance and subcellular distribution, to further test if and how these features may be altered in pathogenic KPNA3 and KPNA4 variants. Results from this project are expected to lead to a better understanding of the cellular significance of KPNA3/4 and the implication of rare pathogenic KPNA3/4 variants in the pathogenesis of associated neurological disorders. Ultimately, this knowledge will contribute to the development of appropriate therapeutics for the treatment of these genetic diseases.

• DFG Programme: Research Grants