Impaired proteasome activity and neurodegeneration with brain iron accumulation in FBXO7 defect

Altres ajuts: This work was funded by Instituto de Salud Carlos III; Ministerio de Educación, Cultura y Deporte; Spanish Foundation per Amor a l'Art (FPAA) grant ; Fundació la Marató de TV3 grants 20143130; and 20143131; Generalitat Valenciana grants OP ERDF of Comunitat Valenciana 2014-2020; and PROMETEO/2018/135. FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS). Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.