Mutations in<i>SDHD</i>lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency

Jackson, Christopher B.; Nuoffer, Jean-Marc; Hahn, Dagmar; Prokisch, Holger; Haberberger, Birgit; Gautschi, Matthias; Häberli, Annemarie; Gallati, Sabina; Schaller, André

doi:10.1136/jmedgenet-2013-101932

Cited by 82 publications

(67 citation statements)

References 29 publications

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“…FA is a mitochondrial disease in which ATP production is reduced due to GAA triplet-repeat expansions in frataxin, a mitochondrial protein involved in the formation of iron-sulfur clusters necessary for respiratory chain complex function (45). Finally, individuals were studied who had genetic deficiency of isoforms of SDH, which serves as respiratory chain complex II (42,46).…”

Section: Methodsmentioning

confidence: 99%

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

DeBrosse¹,

Nanga²,

Wilson³

et al. 2016

JCI Insight

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Section: Methodsmentioning

confidence: 99%

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

DeBrosse¹,

Nanga²,

Wilson³

et al. 2016

JCI Insight

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“…Complex II-related RC deficiencies show a wide clinical spectrum including presentations with isolated myopathy/cardiomyopathy as well as severe multisystem disorders with neurological manifestations. Recently, the first patients with complex II deficiency due to bi-allelic mutations in SDHB and SDHD were described and patients presented with progressive mitochondrial encephalomyopathy (Alston et al 2012;Jackson et al 2014;Helman et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

Grønborg¹,

Darín

Miranda

et al. 2016

JIMD Reports

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Isolated complex II deficiency is a rare cause of mitochondrial disease and bi-allelic mutations in SDHB have been identified in only a few patients with complex II deficiency and a progressive neurological phenotype with onset in infancy. On the other hand, heterozygous SDHB mutations are a well-known cause of familial paraganglioma/pheochromocytoma and renal cell cancer. Here, we describe two additional patients with respiratory chain deficiency due to bi-allelic SDHB mutations. The patients' clinical, neuroradiological, and biochemical phenotype is discussed according to current knowledge on complex II and SDHB deficiency and is well in line with previously described cases, thus confirming the specific neuroradiological presentation of complex II deficiency that recently has emerged. The patients' genotype revealed one novel SDHB mutation, and one SDHB mutation, which previously has been described in heterozygous form in patients with familial paraganglioma/pheochromocytoma and/or renal cell cancer. This is only the second example in the literature where one specific SDHx mutation is associated with both recessive mitochondrial disease in one patient and familial paraganglioma/pheochromocytoma in others. Due to uncertainties regarding penetrance of different heterozygous SDHB mutations, we argue that all heterozygous SDHB mutation carriers identified in relation to SDHB-related leukoencephalopathy should be referred to relevant surveillance programs for paraganglioma/pheochromocytoma and renal cell cancer. The diagnosis of complex II deficiency due to SDHB mutations therefore raises implications for genetic counselling that go beyond the recurrence risk in the family according to an autosomal recessive inheritance.

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“…Patients with mutations in the complex II structural subunit SDHD also showed a milder defect in complex II in fibroblasts than in myoblasts (38). Four assembly factors of complex II that are conserved in yeast and mammals have been identified.…”

Section: Discussionmentioning

confidence: 99%

A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II

Rendón

Antonická

Horvath

et al. 2016

Molecular and Cellular Biology

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bComplex I (NADH ubiquinone oxidoreductase) is a large multisubunit enzyme that catalyzes the first step in oxidative phosphorylation (OXPHOS). In mammals, complex I biogenesis occurs in a stepwise manner, a process that requires the participation of several nucleus-encoded accessory proteins. The FAD-dependent oxidoreductase-containing domain 1 (FOXRED1) protein is a complex I assembly factor; however, its specific role in the assembly pathway remains poorly understood. We identified a homozygous missense mutation, c.1308 G¡A (p.V421M) in FOXRED1 in a patient who presented with epilepsy and severe psychomotor retardation. A patient myoblast line showed a severe reduction in complex I, associated with the accumulation of subassemblies centered around ϳ340 kDa, and a milder decrease in complex II, all of which were rescued by retroviral expression of wild-type FOXRED1. Two additional assembly factors, AIFM1 and ACAD9, coimmunoprecipitated with FOXRED1, and all were associated with a 370-kDa complex I subassembly that, together with a 315-kDa subassembly, forms the 550-kDa subcomplex. Loss of FOXRED1 function prevents efficient formation of this midassembly subcomplex. Although we could not identify subassemblies of complex II, our results establish that FOXRED1 function is both broader than expected, involving the assembly of two flavoprotein-containing OXPHOS complexes, and cell type specific.T he oxidative phosphorylation (OXPHOS) system is responsible for the generation of the majority of cellular ATP. NADH ubiquinone oxidoreductase (complex I), the first enzyme in the pathway, is responsible for the oxidation of NADH. This is coupled with the pumping of protons across the inner mitochondrial membrane, contributing to the formation of the electrochemical gradient that is ultimately used by ATP synthase (complex V) to generate ATP.Complex I is embedded in the inner mitochondrial membrane, forming an L-shaped structure with a membrane domain and a peripheral domain that protrudes into the mitochondrial matrix. It is composed of 44 structural subunits, 7 of which are encoded by the mitochondrial genome (mitochondrial DNA [mtDNA]). In mammals, complex I biogenesis occurs in a stepwise fashion by sequential addition of assembly intermediates (1). Assembly of the holoenzyme requires the import of the 37 nucleus-encoded subunits, followed by sorting, folding, and assembly into the appropriate structural domain of the complex. Seven iron-sulfur clusters are incorporated into five of the core subunits of the peripheral arm (NDUFS1, NDUFS7, NDUFS8, NDUFV1, and NDUFV2), and a flavin mononucleotide (FMN) molecule is inserted noncovalently into NDUFV1.Deficiencies in the activity of complex I, among the most common causes of OXPHOS disorders, are associated with a wide variety of clinical phenotypes that can range from lethal infantile diseases to isolated myopathy or adult-onset neurodegenerative disorders (2). Mutational analyses have identified defects in all 14 core subunits and several of the so-called supernumerary s...

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Mutations inSDHDlead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency

Cited by 82 publications

References 29 publications

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

A Mutation in the Flavin Adenine Dinucleotide-Dependent Oxidoreductase FOXRED1 Results in Cell-Type-Specific Assembly Defects in Oxidative Phosphorylation Complexes I and II

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