BLOC1S1 variants cause lysosomal and autophagic defects resulting in a hypomyelinating leukodystrophy with epileptic encephalopathy - PubMed
3 hours ago
- #autophagy
- #leukodystrophy
- #BLOC1S1
- BLOC1S1 variants cause lysosomal and autophagic defects leading to hypomyelinating leukodystrophy with epileptic encephalopathy.
- Seven distinct BLOC1S1 variants identified in 11 individuals from seven families result in symptoms including early psychomotor delay, hypotonia, spasticity, epileptic encephalopathy, optic atrophy, and leuko-axonopathy with hypomyelination.
- Some individuals exhibit mild features of hypopigmentation and ocular albinism, similar to BLOC-1-related Hermansky-Pudlak syndrome.
- Functional analyses show BLOC1S1 knockout impairs lysosome anterograde transport and autophagy in non-neuronal cells and iPSC-derived neurons.
- Most BLOC1S1 variants reduce expression, decrease assembly with BORC/BLOC-1 subunits, and impair restoration of lysosome transport and autophagy.
- BLOC1S1 knockout reduces pigmentation in melanocytic cells, with five variants partially or fully restoring it.
- Loss of function in BLOC1S1 leads to more pronounced deficits in BORC than BLOC-1 function.
- The study establishes BORCopathies as a distinct disease entity, similar to conditions caused by BORCS8 variants.