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

Paul, Antoine; Drecourt, Anthony; Petit, Floriane; Deguine, D. Dupin; Vasnier, Christelle; Oufadem, Myriam; Masson, Cécile; Bonnet, Crystel; Masmoudi, Saber; Mosnier, Isabelle; Mahieu, L.; Bouccara, D.; Kaplan, Josseline; Challe, Georges; Domange, C.; Mochel, Fanny; Sterkers, Olivier; Gerber, Sylvie; Nitschké, Patrick; Bôle‐Feysot, Christine; Jonard, Laurence; Gherbi, Souad; Mercati, Oriane; Aïssa, Ines; Lyonnet, Stanislas; Rötig, Agnès; Delahodde, Agnès; Marlin, Sandrine

doi:10.1016/j.ajhg.2017.09.007

Cited by 60 publications

(57 citation statements)

References 27 publications

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“…The absence of complex II involvement was remarkable, certainly considering the decreased expression of SDHB. Finally, iron overload, in combination with decreased IRP1 content, was noticed [33]. …”

Section: Mitochondrial Iron–sulfur Biosynthesis (Isc)mentioning

confidence: 99%

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Vanlander

Coster

2018

J Biol Inorg Chem

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Iron–sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron–sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron–sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich’s ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported. In this paper, an overview is given of the clinical, biochemical and genetic aspects reported in humans affected by a defect in iron–sulfur cluster biosynthesis.

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Section: Mitochondrial Iron–sulfur Biosynthesis (Isc)mentioning

confidence: 99%

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Vanlander

Coster

2018

J Biol Inorg Chem

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“…While families with multiple affected siblings or parental consanguinity are thought more likely to have a recessive disorder 9 , there has been no systematic attempt to quantify the recessive burden using large-scale sequencing data and a robust statistical and computational genetic framework.Here we describe an analysis of autosomal recessive coding variants in 7,448 exome-sequenced families from the British Isles, recruited as part of the DDD study. We previously developed a probabilistic method for identifying robust new recessive genes 10 significantly enriched for biallelic (homozygous or compound heterozygous) genotypes, an approach that stands in contrast to the heuristic filtering methods commonly applied [11][12][13][14][15][16][17] . We extend this to estimate the overall burden of recessive causes in this cohort, and compare this between different groups of patients with British European or British Pakistani ancestry.…”

mentioning

confidence: 99%

Quantifying the contribution of recessive coding variation to developmental disorders

Martin

Jones

Stephenson

et al. 2017

Preprint

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Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

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“…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] . Recessive mutations in FDX2 induces a complex phenotype consisting of optic atrophy, reversible leukoencephalopathy, myopathy, and axonal polyneuropathy [233,236] .…”

Section: Iron-sulfur Cluster Biosynthesis and Mitochondrial Iron Homementioning

confidence: 99%

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

Saneto¹

2020

jtgg

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Mitochondrial diseases are clinically and genetically heterogeneous. These diseases were initially described a little over three decades ago. Limited diagnostic tools created disease descriptions based on clinical, biochemical analytes, neuroimaging, and muscle biopsy findings. This diagnostic mechanism continued to evolve detection of inherited oxidative phosphorylation disorders and expanded discovery of mitochondrial physiology over the next two decades. Limited genetic testing hampered the definitive diagnostic identification and breadth of diseases. Over the last decade, the development and incorporation of massive parallel sequencing has identified approximately 300 genes involved in mitochondrial disease. Gene testing has enlarged our understanding of how genetic defects lead to cellular dysfunction and disease. These findings have expanded the understanding of how mechanisms of mitochondrial physiology can induce dysfunction and disease, but the complete collection of disease-causing gene variants remains incomplete. This article reviews the developments in disease gene discovery and the incorporation of gene findings with mitochondrial physiology. This understanding is critical to the development of targeted therapies.

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

Cited by 60 publications

References 27 publications

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Quantifying the contribution of recessive coding variation to developmental disorders

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

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