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Biallelic mutations in FDXR cause neurodegeneration associated with inflammation.

Publication ,  Journal Article
Slone, J; Peng, Y; Chamberlin, A; Harris, B; Kaylor, J; McDonald, MT; Lemmon, M; El-Dairi, MA; Tchapyjnikov, D; Gonzalez-Krellwitz, LA ...
Published in: J Hum Genet
December 2018

Mitochondrial dysfunction lies behind many neurodegenerative disorders, owing largely to the intense energy requirements of most neurons. Such mitochondrial dysfunction may work through a variety of mechanisms, from direct disruption of the electron transport chain to abnormal mitochondrial biogenesis. Recently, we have identified biallelic mutations in the mitochondrial flavoprotein "ferredoxin reductase" (FDXR) gene as a novel cause of mitochondriopathy, peripheral neuropathy, and optic atrophy. In this report, we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy. To investigate the underlying pathogenesis, we examined neurodegeneration in a mouse model. We found that Fdxr mutant mouse brain tissues share pathological changes similar to those seen in patient autopsy material, including increased astrocytes. Furthermore, we show that these abnormalities are associated with increased levels of markers for both neurodegeneration and gliosis, with the latter implying inflammation as a major factor in the pathology of Fdxr mutations. These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment.

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Published In

J Hum Genet

DOI

EISSN

1435-232X

Publication Date

December 2018

Volume

63

Issue

12

Start / End Page

1211 / 1222

Location

England

Related Subject Headings

  • Oxidoreductases
  • Neurodegenerative Diseases
  • Mutation
  • Mice, Transgenic
  • Mice
  • Male
  • Iron-Sulfur Proteins
  • Inflammation
  • Humans
  • Genetics & Heredity
 

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Slone, J., Peng, Y., Chamberlin, A., Harris, B., Kaylor, J., McDonald, M. T., … Huang, T. (2018). Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet, 63(12), 1211–1222. https://doi.org/10.1038/s10038-018-0515-y
Slone, Jesse, Yanyan Peng, Adam Chamberlin, Belinda Harris, Julie Kaylor, Marie T. McDonald, Monica Lemmon, et al. “Biallelic mutations in FDXR cause neurodegeneration associated with inflammation.J Hum Genet 63, no. 12 (December 2018): 1211–22. https://doi.org/10.1038/s10038-018-0515-y.
Slone J, Peng Y, Chamberlin A, Harris B, Kaylor J, McDonald MT, et al. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet. 2018 Dec;63(12):1211–22.
Slone, Jesse, et al. “Biallelic mutations in FDXR cause neurodegeneration associated with inflammation.J Hum Genet, vol. 63, no. 12, Dec. 2018, pp. 1211–22. Pubmed, doi:10.1038/s10038-018-0515-y.
Slone J, Peng Y, Chamberlin A, Harris B, Kaylor J, McDonald MT, Lemmon M, El-Dairi MA, Tchapyjnikov D, Gonzalez-Krellwitz LA, Sellars EA, McConkie-Rosell A, Reinholdt LG, Huang T. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet. 2018 Dec;63(12):1211–1222.
Journal cover image

Published In

J Hum Genet

DOI

EISSN

1435-232X

Publication Date

December 2018

Volume

63

Issue

12

Start / End Page

1211 / 1222

Location

England

Related Subject Headings

  • Oxidoreductases
  • Neurodegenerative Diseases
  • Mutation
  • Mice, Transgenic
  • Mice
  • Male
  • Iron-Sulfur Proteins
  • Inflammation
  • Humans
  • Genetics & Heredity