Movement disorders : official journal of the Movement Disorder Society · 2026
A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.
СтатьяНазвание и аннотация: Перевод в очереди
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Yang Lingzi, Chi Haoran, Zhang Yifan, Wu Dongmei, Hu Yang, Guo Jianhe, He Yunsen, Fan Jinhua, Lv Keyi, Cheng Feifei, Xiao Nong, Peng Qiongling, Dong Yanling, Wang Longlun, Wu Bo, Zhong Min, Liu Tongfei
Аннотация
BACKGROUND: SPG4, the most common hereditary spastic paraplegia caused by SPAST variants, exhibits extreme age-at-onset variability, indicative of uncharacterized genetic modifiers. The GJA1R148Q variant (linked to oculodentodigital dysplasia) may modulate SPG4 pathogenesis, yet its underlying molecular mechanism remains undefined.
OBJECTIVE: We investigated the molecular mechanism by which GJA1R148Q accelerates early SPG4 onset in a proband with dual SPAST and GJA1 variants, and validated its function as a disease modifier for SPG4.
METHODS: We performed comprehensive clinical phenotyping, segregation analysis, coimmunoprecipitation, ubiquitination analyses, CRISPR-mediated correction in patient induced pluripotent stem cell2013derived organoids, and a targeted deubiquitinase screen.
RESULTS: The GJA1R148Q enhanced the physical interaction between SPASTIN and GJA1, accelerated the degradation of deubiquitinase valosin-containing protein interacting protein 1 (VCPIP1), and thereby reduced SPASTIN levels. CRISPR-based reversion of the R148Q restored SPASTIN levels and rescued microtubule-severing function. Notably, maternal relatives carrying the GJA1R148Q allele alone exhibited no neurological abnormalities.
CONCLUSIONS: The GJA1R148Q variant, although non-neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1-VCPIP1-SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. © 2026 International Parkinson and Movement Disorder Society.
OBJECTIVE: We investigated the molecular mechanism by which GJA1R148Q accelerates early SPG4 onset in a proband with dual SPAST and GJA1 variants, and validated its function as a disease modifier for SPG4.
METHODS: We performed comprehensive clinical phenotyping, segregation analysis, coimmunoprecipitation, ubiquitination analyses, CRISPR-mediated correction in patient induced pluripotent stem cell2013derived organoids, and a targeted deubiquitinase screen.
RESULTS: The GJA1R148Q enhanced the physical interaction between SPASTIN and GJA1, accelerated the degradation of deubiquitinase valosin-containing protein interacting protein 1 (VCPIP1), and thereby reduced SPASTIN levels. CRISPR-based reversion of the R148Q restored SPASTIN levels and rescued microtubule-severing function. Notably, maternal relatives carrying the GJA1R148Q allele alone exhibited no neurological abnormalities.
CONCLUSIONS: The GJA1R148Q variant, although non-neurological in isolation, acts as a disease modifier that precipitates SPG4 by exacerbating SPASTIN haploinsufficiency through destabilization of VCPIP1, positioning GJA1-VCPIP1-SPASTIN signaling as a potential therapeutic axis for SPG4 treatment. © 2026 International Parkinson and Movement Disorder Society.