Four subtypes of disease-causing missense mutations underlie pathogenic protein interactions in neurodegenerative VPS13A disease

Xing Lin; Yuta Ryoden; Chigure Suzuki; Hiroyuki Ishikawa; Takaharu Sakuragi; Yasuo Uchiyama; Shigekazu Nagata

doi:10.1172/JCI200890

Four subtypes of disease-causing missense mutations underlie pathogenic protein interactions in neurodegenerative VPS13A disease

Xing Lin,¹ Yuta Ryoden,¹ Chigure Suzuki,² Hiroyuki Ishikawa,¹ Takaharu Sakuragi,¹ Yasuo Uchiyama,³ and Shigekazu Nagata¹

Published March 24, 2026 - More info

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Abstract

VPS13A is an intracellular lipid transfer protein comprising over 3,000 amino acids. Mutations in human VPS13A cause VPS13A disease, a neurodegenerative disorder that affects movement and cognition. VPS13A forms a complex with the membrane protein XK to mediate ATP-induced phospholipid scrambling in the plasma membrane. Here, we established a mouse cell system expressing full-length mouse VPS13A and examined its interaction with XK. Mutational analysis revealed that VPS13A binds to XK through a C-terminal β-strand that interacts with a β-hairpin in the central region of XK, an interaction essential for scramblase activity. The XK paralog XKR2, which contains a similar β-hairpin structure, also associates with VPS13A and supports phospholipid scrambling. We analyzed ten mouse VPS13A variants corresponding to patient mutations and classified them into four groups: (1) L67P, I90K, and W2453R, which showed reduced expression; (2) A1091P and M3080R, which were normally expressed but lacked scramblase activity; (3) S1446P, Q2689H, Y2713C, and R3084H, which modestly impaired expression or activity; and (4) I2763R, which altered cell size, and disrupted ER independently of XK. These findings define the VPS13A–XK interaction interface, clarify the functional impact of disease-causing mutations, and reveal an unexpected gain-of-function mutation of a VPS13A variant.

Four subtypes of disease-causing missense mutations underlie pathogenic protein interactions in neurodegenerative VPS13A disease

Xing Lin,¹ Yuta Ryoden,¹ Chigure Suzuki,² Hiroyuki Ishikawa,¹ Takaharu Sakuragi,¹ Yasuo Uchiyama,³ and Shigekazu Nagata¹

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Four subtypes of disease-causing missense mutations underlie pathogenic protein interactions in neurodegenerative VPS13A disease

Xing Lin,1 Yuta Ryoden,1 Chigure Suzuki,2 Hiroyuki Ishikawa,1 Takaharu Sakuragi,1 Yasuo Uchiyama,3 and Shigekazu Nagata1

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Xing Lin,¹ Yuta Ryoden,¹ Chigure Suzuki,² Hiroyuki Ishikawa,¹ Takaharu Sakuragi,¹ Yasuo Uchiyama,³ and Shigekazu Nagata¹