X‐linked <i>NDUFA1</i> gene mutations associated with mitochondrial encephalomyopathy

Fernández-Moreira, Daniel; Ugalde, Cristina; Smeets, Roel; Rodenburg, Richard J.; López‐Laso, Eduardo; Ruiz-Falcó, María Luz; Briones, Paz; Martín, Miguel; Smeitink, Jan A.M.; Arenas, Joaquı́n

doi:10.1002/ana.21036

Cited by 119 publications

(61 citation statements)

References 46 publications

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“…2 All other proteins contributing to OXPHOS function are autosomally encoded, therefore defects can occur within nuclear or mitochondrial-encoded genes. Mitochondrial disease is genetically and clinically heterogeneous, and can follow mendelian or X-linked inheritance patterns, or be strictly matrilineal in the case of mtDNA mutations; [3][4][5] clinical presentations range from isolated organ involvement (deafness, diabetes and cardiomyopathy) to multisystem, syndromic presentations dominated by muscle and CNS involvement. 6,7 Such heterogeneity can mean that identifying the causative genetic defect is problematic.…”

Section: Introductionmentioning

confidence: 99%

Maternally inherited mitochondrial DNA disease in consanguineous families

Alston

Morris

et al. 2011

Eur J Hum Genet

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Section: Introductionmentioning

confidence: 99%

Maternally inherited mitochondrial DNA disease in consanguineous families

Alston

Morris

et al. 2011

Eur J Hum Genet

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“…[Dunning et al, 2007;Saada et al, 2008;Pagliarini et al, 2008;Sugiana et al, 2008] and in 12 nuclear encoded subunits of complex I [reviewed in Janssen et al, 2006;Fernandez-Moreira et al, 2007;Hoefs et al, 2008;Berger et al, 2008]. However, molecular diagnosis is still lacking for 50% of the patients [Thorburn, 2004].…”

Section: Introductionmentioning

confidence: 99%

Baculovirus complementation restores a novelNDUFAF2mutation causing complex I deficiency

et al. 2009

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Mitochondrial complex I deficiency is the most common defect of the OXPHOS system. We report a patient from consanguineous parents with a complex I deficiency expressed in skin fibroblasts. Homozygosity mapping revealed several homozygous regions with candidate genes, including the gene encoding an assembly factor for complex I, NDUFAF2. Screening of this gene on genomic DNA revealed a homozygous stop-codon resulting in a truncation of the protein at position 38. The mutation causes a severely reduced activity and a disturbed assembly of complex I. A baculovirus containing the GFP-tagged wild-type NDUFAF2 gene was used to prove the functional consequences of the mutation. The expression and activity of complex I was almost completely rescued by complementation of the patient fibroblasts with the baculovirus. Therefore, the homozygous substitution in NDUFAF2 is the disease-causing mutation, which results in a complex I deficiency in the fibroblasts of the patient.

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“…Some assembly factor mutations also impair its activity (16). Other pathogenic mutations are found in all of the core subunits, and in 10 supernumerary subunits (NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFB3, NDUFB9, NDUFS4, and NDUFS6) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Those in supernumerary subunits NDUFA2, NDUFA10, NDUFS4, and NDUFS6 are associated with a reduced level of intact complex and accumulation of subcomplexes, indicating a defect in assembly or stability of the complex, or both.…”

mentioning

confidence: 99%

Assembly factors for the membrane arm of human complex I

Andrews

Carroll

Ding

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

125

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Mitochondrial respiratory complex I is a product of both the nuclear and mitochondrial genomes. The integration of seven subunits encoded in mitochondrial DNA into the inner membrane, their association with 14 nuclear-encoded membrane subunits, the construction of the extrinsic arm from 23 additional nuclear-encoded proteins, iron-sulfur clusters, and flavin mononucleotide cofactor require the participation of assembly factors. Some are intrinsic to the complex, whereas others participate transiently. The suppression of the expression of the NDUFA11 subunit of complex I disrupted the assembly of the complex, and subcomplexes with masses of 550 and 815 kDa accumulated. Eight of the known extrinsic assembly factors plus a hydrophobic protein, C3orf1, were associated with the subcomplexes. The characteristics of C3orf1, of another assembly factor, TMEM126B, and of NDUFA11 suggest that they all participate in constructing the membrane arm of complex I. mitochondria | respiratory chain | NADH:ubiquinone oxidoreductase

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X‐linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy

Abstract: Mutations in the X-linked NDUFA1 gene result in complex I defect and encephalomyopathy. Assembly/stability analysis might give an explanation for the different clinical phenotypes and become useful for future diagnostic purposes.

Cited by 119 publications

References 46 publications

Maternally inherited mitochondrial DNA disease in consanguineous families

Maternally inherited mitochondrial DNA disease in consanguineous families

Baculovirus complementation restores a novelNDUFAF2mutation causing complex I deficiency

Assembly factors for the membrane arm of human complex I

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