A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

Ogilvie, Isla; Kennaway, Nancy G.; Shoubridge, Eric A.

doi:10.1172/jci26020

Cited by 261 publications

(246 citation statements)

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“…Complex I catalyses the first step in the mitochondrial respiratory chain, and a homozygous mutation in this gene was found in a child with severe progressive leukoencephalopathy. 55 Disruption and functional loss or a dominant interfering effect of a mutant copy of NDUFAF2 may cause neurometabolic deficiency resulting in an allelic disorder with an ADHD phenotype. Patient 51 carries a B500 kb duplication located at 11q13.4 and inherited from the affected mother.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

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Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domaincontaining protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 a subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a B3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

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Section: Discussionmentioning

confidence: 99%

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

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“…However, genes encoding accessory subunits, such as NDUFS4, NDUFS6, NDUFA1, NDUFA2, and NDUFA11, may also contain pathogenic mutations. [8][9][10]29,30 NDUFA10 also belongs to these accessory subunits.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] Furthermore, mutations have been described in eight assembly factors (NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, C8orf38, C20orf7, ACAD9, and NDUBPL) of this complex and in an uncharacterized protein (FOXRED1) causing complex I deficiency. [9][10][11][12][13][14][15][16] Although pathogenic mutations have been described in accessory subunits, the function of these subunits is not exactly known yet. It has been suggested that some are important for the biogenesis of complex I.…”

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confidence: 99%

NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease

et al. 2010

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Mitochondrial complex I deficiency is the most common defect of the oxidative phosphorylation system. We report a patient with Leigh syndrome who showed a complex I deficiency expressed in cultured fibroblasts and muscle tissue. To find the genetic cause of the complex I deficiency, we screened the mitochondrial DNA and the nuclear-encoded subunits of complex I. We identified compound-heterozygous mutations in the NDUFA10 gene, encoding an accessory subunit of complex I. The first mutation disrupted the start codon and the second mutation resulted in an amino acid substitution. The fibroblasts of the patient displayed decreased amount and activity, and a disturbed assembly of complex I. These results indicate that NDUFA10 is a novel candidate gene to screen for disease-causing mutations in patients with complex I deficiency.

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“…This process requires additional proteins, termed 'assembly factors', which aid complex I assembly [46]. The first pathogenic human mutation in a CI assembly factor was found in NDUFAF2 [47]. Since this initial discovery, several other pathogenic mutations have been identified in CI assembly factor genes, including NDUFAF1 [48], NDUFAF3 [49], NDUFAF4 [50], NDUFAF5 [51], NDUFAF6 [52], FOXRED1 [53], ACAD9 [54] and NUBPL [53] (Table 1).…”

Section: Oxphos Complex Imentioning

confidence: 99%

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

2016

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SynopsisMitochondria provide the main source of energy to eukaryotic cells, oxidizing fats and sugars to generate ATP . Mitochondrial fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two metabolic pathways which are central to this process. Defects in these pathways can result in diseases of the brain, skeletal muscle, heart and liver, affecting approximately 1 in 5000 live births. There are no effective therapies for these disorders, with quality of life severely reduced for most patients. The pathology underlying many aspects of these diseases is not well understood; for example, it is not clear why some patients with primary FAO deficiencies exhibit secondary OXPHOS defects. However, recent findings suggest that physical interactions exist between FAO and OXPHOS proteins, and that these interactions are critical for both FAO and OXPHOS function. Here, we review our current understanding of the interactions between FAO and OXPHOS proteins and how defects in these two metabolic pathways contribute to mitochondrial disease pathogenesis.Key words: disease, mitochondria, protein complex assembly, protein interactions, supercomplex. MITOCHONDRIAL METABOLISMMitochondria occupy almost all human cell types and are involved in essential metabolic and cellular processes, including calcium and iron homoeostasis, apoptosis, innate immunity and haeme biosynthesis [1]. However, the primary function of mitochondria is the production of energy in the form of ATP [2][3][4]. ATP is the body's energy currency, playing vital roles in cell differentiation, growth and reproduction, thermogenesis and powering the contraction of muscles for movement [1]. In humans, ATP is produced by two different processes; through the breakdown of glucose or other sugars in Abbreviations: ACAD9, acyl-CoA dehydrogenase 9; BN-PAGE, blue native polyacrylamide gel electrophoresis; CACT, carnitine acylcarnitine translocase; CI, oxidative phosphorylation complex I (NADH: ubiquinone oxidoreductase, EC 1.6.5.3); CII, oxidative phosphorylation complex II (succinate: ubiquinone oxidoreductase, EC 1.3.5.1); CIII, oxidative phosphorylation complex III (ubiquinol: ferricytochrome c oxidoreductase, EC 1.10.2.2); CIV, oxidative phosphorylation complex IV (cytochrome c oxidase, EC 1.9.3.1); COPP , complex one phylogenetic profile; CPT1, carnitine O-palmitoyltransferase 1; CPT2, carnitine O-palmitoyltransferase 2; CV, OXPHOS complex V (FoF 1 -ATP synthetase, EC; 3.6.3.14); ECHS1, enoyl-CoA hydratase, short chain 1, mitochondrial; ECI1, enoyl-CoA delta isomerase, 1; ETF, electron transfer flavoprotein; ETFA, electron transfer flavoprotein alpha subunit; ETFB, electron transfer flavoprotein beta subunit; ETF-QO, electron transfer flavoprotein: ubiquinone oxidoreductase; FAD, flavin adenine dinucleotide; FADH 2 , reduced flavin adenine dinucleotide; FAO, fatty acid β-oxidation; H 2 O, water; HADH, hydroxyacyl-CoA dehydrogenase; KAT, 3-ketoacyl-CoA thiolase, mitochondrial; LCAD, long chain acyl-CoA dehydrogenase; LCEH, long chain enoyl-CoA hydra...

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A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy

Cited by 261 publications

References 51 publications

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

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