Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy

Abstract

Iron–sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe–S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.

Integrated analysis of the molecular pathogenesis of FDXR-associated disease

“…Retinal H&Estained sections displayed normal organization of retinal structure, but thinner inner retinas and noticeable retinal ganglion cell (RGC) loss in the GCL at 12 months (Fig. 1c), in agreement with our previous data 19 . By contrast, there was no significant difference in the number of RGC layer nuclei between Fdxr +/+ and Fdxr −/− mice at 3 weeks ( Fig.…”

“…Fdxr mutations cause a progressive optic neuropathy and optic transport defects in Fdxr −/− mice The naturally occurring Fdxr R389Q/R389Q mouse line 22 harbors a homozygous R389Q missense mutation in Fdxr that is allelic to the common human mutation p.R392W 19 . To better characterize the optic neuropathy associated with FDXR mutation, we examined the retina of Fdxr R389Q/R389Q mutant mice (hereafter referred to as "Fdxr −/− " mice) with an imaging technique, optical coherence tomography (OCT), that can acquire cross-sectional tomographic images of the retina in vivo 23,24 .…”

“…However, despite such tantalizing clues and a welldefined biochemical function, the exact consequences of FDXR mutation in patients have remained largely elusive. Using data from a large number of families, we recently demonstrated that biallelic mutations in the FDXR gene lead to gait abnormalities and visual impairment 19 . In a parallel analysis, we showed that mice possessing a naturally occurring mutation in Fdxr presented with neurological abnormalities, loss of visual acuity and gait abnormalities, reminiscent of the phenotypes observed in patients.…”

“…In a parallel analysis, we showed that mice possessing a naturally occurring mutation in Fdxr presented with neurological abnormalities, loss of visual acuity and gait abnormalities, reminiscent of the phenotypes observed in patients. Enzymatic assays in both patient fibroblasts and in tissues from Fdxr mutant mice indicated multiple biochemical and metabolic consequences of FDXR mutation, including reductions in ATP production and ETC complex activities, along with a significant increase in the production of reactive oxygen species (ROS) 19 . Furthermore, our followup study showed that FDXR mutation is linked to inflammation and gliosis in the CNS, providing clues as to the possible mechanism of FDXR pathology 20 .…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…Ferredoxin reductase (FDXR) donates electrons from NADPH to homologous ferredoxins, FDX1 and FDX2, and initiates the 2Fe/2S scaffold complex. Variants in FDXR diminished iron-sulfur cluster assembly and induce mitochondrial iron overload [234] . The diminished cluster assembly phenotypically gives rise to optic atrophy and sensory neuropathy [235,236] .…”