A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels

SPG4, the most common hereditary spastic paraplegia caused by SPAST variants, exhibits extreme age-at-onset variability, indicative of uncharacterized genetic modifiers. The GJA1^R148Q variant (linked to oculodentodigital dysplasia) may modulate SPG4 pathogenesis, yet its underlying molecular mechanism remains undefined.

We investigated the molecular mechanism by which GJA1^R148Q accelerates early SPG4 onset in a proband with dual SPAST and GJA1 variants, and validated its function as a disease modifier for SPG4.

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.

The GJA1^R148Q 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 GJA1^R148Q allele alone exhibited no neurological abnormalities.

The GJA1^R148Q 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.