A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.
A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.
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The study site has not been established. Author addresses may differ from where the research occurred.
Chongqing, CN · Author affiliation
Department of Rehabilitation, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.Location evidence
Shanghai, CN · Author affiliation
Department of Neurosurgery, Sichuan Lansheng Brain Hospital & Shanghai Lansheng Brain Hospital Investment Co., Ltd, Chengdu, China.Location evidence
Chengdu, CN · Author affiliation
Department of Neurosurgery, Sichuan Lansheng Brain Hospital & Shanghai Lansheng Brain Hospital Investment Co., Ltd, Chengdu, China.Location evidence
Fuling, CN · Author affiliation
Central Laboratory, Chongqing University Fuling Hospital, Chongqing University, Fuling, China.Location evidence
Shenzhen, CN · Author affiliation
Department of Child Healthcare, Shenzhen Bao'an Women's and Children's Hospital, Shenzhen, China.Location evidence
Bao'an, CN · Author affiliation
Department of Child Healthcare, Shenzhen Bao'an Women's and Children's Hospital, Shenzhen, China.Location evidence
Jiangxi, CN · Author affiliation
Department of Rehabilitation, Jiangxi Children's Medical Center, Jiangxi Provincial Key Laboratory of Birth Defect for Prevention and Control, Nanchang, China.Location evidence
Nanchang, CN · Author affiliation
Department of Rehabilitation, Jiangxi Children's Medical Center, Jiangxi Provincial Key Laboratory of Birth Defect for Prevention and Control, Nanchang, China.Location evidence
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Original abstract
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.