Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene

Birch‐Machin, Mark A.; Taylor, Robert W.; Cochran, Bruce; Ackrell, Brian A.C.; Turnbull, Douglass M.

doi:10.1002/1531-8249(200009)48:3<330::aid-ana7>3.0.co;2-a

Cited by 134 publications

(63 citation statements)

References 22 publications

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“…18 Interestingly enough, a late-onset optic atrophy has also been ascribed to a heterozygous mutation in SDHA in two patients with 50% residual SDH activity. 19 In none of these cases was the presence of tumour reported.…”

Section: Sdh Deficiencies: Reduced Electron Flow And/or Increased Oxymentioning

confidence: 99%

Succinate dehydrogenase and human diseases: new insights into a well-known enzyme

2002

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Inherited defects of the mitochondrial succinate dehydrogenase (SDH) in humans are associated with striking variable clinical presentations ranging from early-onset devastating encephalomyopathy to tumour susceptibility in adulthood, or optic atrophy in the elderly. Although different genes encoding the four subunits of the SDH have been found mutated in association with these different phenotypes, we propose that the wide clinical spectrum actually originates from the specific roles of the SDH in the respiratory chain and the mitochondria. In particular, beside its function in the Krebs cycle and the respiratory chain, the specific redox properties of the enzyme could confer to the SDH a specific function in superoxide handling.

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Section: Sdh Deficiencies: Reduced Electron Flow And/or Increased Oxymentioning

confidence: 99%

Succinate dehydrogenase and human diseases: new insights into a well-known enzyme

2002

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“…Alteration in SDH enzyme kinetics has also been shown in human SDH1 mutations. A point mutation A409C in the succinate binding site of SDH1 led to a 50% reduction of SDH activity and caused optic atrophy and myopathy (Birch-Machin et al, 2000;Sun et al, 2005). Mutation of R554Y in SDH1 caused an unstable SDH1 helix domain and also a 50% decrease in SDH activity and loss of ATP activation resulting in the neurodegenerative disorder Leigh-like syndrome (Bourgeron et al, 1995;Sun et al, 2005).…”

Section: Low Concentrations Of Sa Increase Sqr Activitymentioning

confidence: 99%

Salicylic Acid-Dependent Plant Stress Signaling via Mitochondrial Succinate Dehydrogenase

et al. 2017

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Mitochondria are known for their role in ATP production and generation of reactive oxygen species, but little is known about the mechanism of their early involvement in plant stress signaling. The role of mitochondrial succinate dehydrogenase (SDH) in salicylic acid (SA) signaling was analyzed using two mutants: disrupted in stress response1 (dsr1), which is a point mutation in SDH1 identified in a loss of SA signaling screen, and a knockdown mutant (sdhaf2) for SDH assembly factor 2 that is required for FAD insertion into SDH1. Both mutants showed strongly decreased SA-inducible stress promoter responses and low SDH maximum capacity compared to wild type, while dsr1 also showed low succinate affinity, low catalytic efficiency, and increased resistance to SDH competitive inhibitors. The SA-induced promoter responses could be partially rescued in sdhaf2, but not in dsr1, by supplementing the plant growth media with succinate. Kinetic characterization showed that low concentrations of either SA or ubiquinone binding site inhibitors increased SDH activity and induced mitochondrial H 2 O 2 production. Both dsr1 and sdhaf2 showed lower rates of SA-dependent H 2 O 2 production in vitro in line with their low SA-dependent stress signaling responses in vivo. This provides quantitative and kinetic evidence that SA acts at or near the ubiquinone binding site of SDH to stimulate activity and contributes to plant stress signaling by increased rates of mitochondrial H 2 O 2 production, leading to part of the SA-dependent transcriptional response in plant cells.

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“…However, one other mutation affecting the FAD binding has been previously reported in patients from a family affected by late-onset optic atrophy, ataxia, and a proximal myopathy. 5 Surprisingly, this mutation, c.1375C4T (p.Arg408Cys), was found as a heterozygous mutation with no other mutations in the SDHA coding sequence and normal levels of both SDHA mRNA and protein. The p.Arg408Cys mutation was found to affect the specific activity of CII, likely by affecting the FAD binding.…”

Section: Discussionmentioning

confidence: 93%

“…Most of these patients showed a regression starting in the first year of life accompanied by one or more of the following signs and symptoms: ataxia, dystonia, myopathy, optic atrophy, hepatomegaly, seizures, lactic academia, and elevated citric acid cycle intermediates in urine. [4][5][6][7][8][9][10][11] In addition, a Bedouin family with 15 members having isolated dilated cardiomyopathy has been described, 12 and a single patient with cardiomyopathy and leukodystrophy. 13 A mutation in the CII assembly factor SDHAF1 (see Ghezzi et al 14 ) and recently also in SDHB 13 and SDHD 15 have also been found to cause LS or LS-like symptoms, although so far LS was not found in association with mutations in SDHC.…”

Section: Introductionmentioning

confidence: 99%

SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors

et al. 2014

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Defects in complex II of the mitochondrial respiratory chain are a rare cause of mitochondrial disorders. Underlying autosomal-recessive genetic defects are found in most of the 'SDHx' genes encoding complex II (SDHA, SDHB, SDHC, and SDHD) and its assembly factors. Interestingly, SDHx genes also function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. In these cases, the affected patients are carrier of a heterozygeous SDHx germline mutation. Until now, mutations in SDHx associated with mitochondrial disease have not been reported in association with hereditary tumors and vice versa. Here, we characterize four patients with isolated complex II deficiency caused by mutations in SDHA presenting with multisystem mitochondrial disease including Leigh syndrome (LS) and/or leukodystrophy. Molecular genetic analysis revealed three novel mutations in SDHA. Two mutations (c.64-2A4G and c.1065-3C4A) affect mRNA splicing and result in loss of protein expression. These are the first mutations described affecting SDHA splicing. For the third new mutation, c.565T4G, we show that it severely affects enzyme activity. Its pathogenicity was confirmed by lentiviral complementation experiments on the fibroblasts of patients carrying this mutation. It is of special interest that one of our LS patients harbored the c.91C4T (p.Arg31*) mutation that was previously only reported in association with paragangliomas and pheochromocytomas, tightening the gap between these two rare disorders. As tumor screening is recommended for SDHx mutation carriers, this should also be considered for patients with mitochondrial disorders and their family members.

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Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene

Cited by 134 publications

References 22 publications

Succinate dehydrogenase and human diseases: new insights into a well-known enzyme

Succinate dehydrogenase and human diseases: new insights into a well-known enzyme

Salicylic Acid-Dependent Plant Stress Signaling via Mitochondrial Succinate Dehydrogenase

SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors

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