3 years ago

FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases

FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases
Cécile Masson, Laurence Jonard, Delphine Dupin Deguine, Anthony Drecourt, Agnès Delahodde, Sylvie Gerber, Olivier Sterkers, Agnès Rötig, Crystel Bonnet, Stanislas Lyonnet, Souad Gherbi, Christelle Domange, Floriane Petit, Sandrine Marlin, Patrick Nitschke, Fanny Mochel, Antoine Paul, Georges Challe, Laurence Mahieu, Isabelle Mosnier, Josseline Kaplan, Myriam Oufadem, Oriane Mercati, Saber Masmoudi, Ines Ben Aissa, Christine Bole-Feysot, Christelle Vasnier, Didier Bouccara

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.

Publisher URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30376-2

DOI: 10.1016/j.ajhg.2017.09.007

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