In humans, mutations in the VPS13A gene are known to cause VPS13A disease, a neurodegenerative disorder characterized by the chronic and progressive worsening of motor and cognitive functions. The research group led by Shigekazu Nagata has previously reported the mechanism by which a cytoplasmic complex of VPS13A proteins induces scramblase activity at the plasma membrane. However, the relationship among the disease, the complex, and scramblase activity has remained unclear.

The authors analyzed clinically reported nonsense mutations and found that complex formation is required for scramblase activity. Furthermore, they identified key residue pairs involved in complex formation through analysis based on an AlphaFold 3 structural prediction model. They also performed a comprehensive analysis of patient-reported missense mutations and proposed that these mutations can be classified into four types.
(online publication in Journal of Clinical Investigation on March 24, 2026) 

Contact

Prof. Shigekazu Nagata

snagataifrec.osaka-u.ac.jp

Biochemistry & Immunology