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

Am J Hum Genet. 2017 Oct 5;101(4):630-637. doi: 10.1016/j.ajhg.2017.09.007.

Antoine Paul ¹, Anthony Drecourt ¹, Floriane Petit ¹, Delphine Dupin Deguine ², Christelle Vasnier ³, Myriam Oufadem ¹, Cécile Masson ¹, Crystel Bonnet ⁴, Saber Masmoudi ⁵, Isabelle Mosnier ⁶, Laurence Mahieu ⁷, Didier Bouccara ⁶, Josseline Kaplan ¹, Georges Challe ⁸, Christelle Domange ⁹, Fanny Mochel ¹⁰, Olivier Sterkers ⁶, Sylvie Gerber ¹, Patrick Nitschke ¹, Christine Bole-Feysot ¹, Laurence Jonard ¹¹, Souad Gherbi ¹², Oriane Mercati ¹², Ines Ben Aissa ¹², Stanislas Lyonnet ¹³, Agnès Rötig ¹, Agnès Delahodde ³, Sandrine Marlin ¹⁴

Affiliations

1 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
2 Service de Génétique Médicale, Hôpital Purpan, 40031 Toulouse, France.
3 Institute for Integrative Biology of the Cell, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Université Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette Cedex, France.
4 UMRS 1120, Institut de la Vision, 75012 Paris, France.
5 Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology of Sfax, 1177 Sfax, Tunisia.
6 Service d'Oto-Rhino-Laryngologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France.
7 Service d'Ophtalmologie, Hôpital Rangueil, 40031 Toulouse, France.
8 Service d'Ophtalmologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France.
9 Service d' d'Oto-Rhino-Laryngologie, Hôpital Lariboisière, 75475 Paris, France.
10 Département de Génétique, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France.
11 Service de Génétique, Laboratoire de Génétique Moléculaire, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
12 Centre de Référence des Surdités Génétiques, Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
13 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France.
14 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Centre de Référence des Surdités Génétiques, Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; Service de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France. Electronic address: [email protected].

PMID: 28965846 DOI: 10.1016/j.ajhg.2017.09.007

Abstract

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.

Keywords

ARH1; Auditory neuropathy; FDXR; Fe-S cluster synthesis; iron overload; iron-sulfur cluster; mitochondria; optic atrophy.

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