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

Ann Clin Transl Neurol. 2020 Aug;7(8):1436-1442. doi: 10.1002/acn3.51095. Epub 2020 Aug 6.

Abstract

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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Consanguinity
  • Epilepsy / enzymology
  • Epilepsy / genetics
  • Epilepsy / pathology
  • Epilepsy / physiopathology
  • F-Box Proteins / genetics*
  • Female
  • Humans
  • Iron Metabolism Disorders* / enzymology
  • Iron Metabolism Disorders* / genetics
  • Iron Metabolism Disorders* / pathology
  • Iron Metabolism Disorders* / physiopathology
  • Neuroaxonal Dystrophies* / enzymology
  • Neuroaxonal Dystrophies* / genetics
  • Neuroaxonal Dystrophies* / pathology
  • Neuroaxonal Dystrophies* / physiopathology
  • Paraplegia / enzymology
  • Paraplegia / genetics
  • Paraplegia / pathology
  • Paraplegia / physiopathology
  • Parkinsonian Disorders* / enzymology
  • Parkinsonian Disorders* / genetics
  • Parkinsonian Disorders* / pathology
  • Parkinsonian Disorders* / physiopathology
  • Proteasome Endopeptidase Complex / metabolism*
  • Spinocerebellar Degenerations / enzymology
  • Spinocerebellar Degenerations / genetics
  • Spinocerebellar Degenerations / pathology
  • Spinocerebellar Degenerations / physiopathology
  • Syndrome
  • Young Adult

Substances

  • F-Box Proteins
  • FBXO7 protein, human
  • Proteasome Endopeptidase Complex

Supplementary concepts

  • Neurodegeneration with brain iron accumulation (NBIA)

Grants and funding

This work was funded by Instituto de Salud Carlos III grants PI18/00147 and PI18/01319; Ministerio de Educación, Cultura y Deporte grant FPU‐PhD fellowship FPU 15/00964; 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.