Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes

Simon, Mariella; Eftekharian, Shaya S.; Stover, Alexander E.; Osborne, Aaron Fletcher; Braffman, B.; Chang, Richard Y.; Wang, Raymond; Steenari, Maija; Tang, Sha; Hwu, Wuh‐Liang; Taft, Ryan J.; Benke, Paul J.; Abdenur, José E.

doi:10.1016/j.ymgme.2018.11.001

Cited by 41 publications

(66 citation statements)

References 31 publications

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“…The complicated assembly of so many subunits requires a number of assembly factors that are not part of the final structure of complex I. Currently, at least 15 known or putative complex I assembly factors have been described and variants in nine of these were associated with isolated complex I deficiency due to impaired complex I biogenesis [9,11,12]. One of those assembly factors is FOXRED1, a 486-amino acid FAD-dependent oxidoreductase.…”

Section: Introductionmentioning

confidence: 99%

Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency

Gouveia

Borges

Gutiérrez-Solana

et al. 2019

JCM

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Complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase) is the largest complex of the mitochondrial oxidative phosphorylation system (OXPHOS) system. Forty-four subunits encoded in nuclear and mitochondrial genomes compose this multiprotein complex, its assembly being a highly complex process involving at least 15 additional nuclear encoded assembly factors. Complex I deficiency is a mitochondrial disorder usually associated with early-onset severe multisystem disorders characterized by highly variable clinical manifestations. Flavin adenine dinucleotide (FAD)-dependent oxidoreductase domain-containing protein 1 (FOXRED1) is a complex I assembly factor. To date, only five patients with mitochondrial complex I deficiency due to mutations in FOXRED1 have been characterized. Here, we describe a child with ataxia, epilepsy and psychomotor developmental delay carrying two heterozygous FOXRED1 variants, c.920G>A (p.Gly307Glu) and c.733+1G>A. We demonstrate the molecular mechanism supporting the pathogenicity of the FOXRED1 variants, showing a clear deficiency of complex I activity. The reduction in the steady-state level of complex I holoenzyme in patient fibroblasts, confirmed the pathogenicity of the variants and showed the molecular mechanism behind their pathogenicity. A comparison of the clinical presentation of the index case with the previously described cases allowed deepening our knowledge about the clinical variability associated with FOXRED1 defects.

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Section: Introductionmentioning

confidence: 99%

Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency

Gouveia

Borges

Gutiérrez-Solana

et al. 2019

JCM

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“…With interest we read the article by Simon et al about 4 patients with complex-I deficiency due to mutations in the NDUFAF5 gene [1]. The phenotype and the outcome of these 4 patients varied considerably [1]. We have the following comments and concerns.…”

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confidence: 99%

“…MRI in patient-4 revealed DWI hyperintense serpiginous lesions [1]. To clarify if these lesions represent a cytotoxic or vasogenic edema it would be helpful to know the results of the ADC maps.…”

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confidence: 99%

“…In patient-3 arterial hypertension was attributed to administration of ACTH (Table 1) [1]. However, patient-1 had arterial hypertension in the absence of a plausible trigger.…”

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confidence: 99%

“…Both Taiwanese patients had severe hyponatremia (Table 1) [1]. We should be informed if this was due to primary or secondary hypoaldosteronism, or due to pituitary insufficiency, occasionally occurring as endocrine manifestations of a MID [4].…”

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NDUFAF5 variants manifest phenotypically heterogeneously

Finsterer

2019

Molecular Genetics and Metabolism Reports

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Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5‐related disorders

Legro

Kumar

Aliu

2021

American J of Med Genetics Pt A

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NDUFAF5 encodes a Complex I assembly factor which is critical to the modification of a core subunit, NDUFS7, in early Complex I factor assembly. Mutations in NDUFAF5 have been previously shown to cause Complex I deficiency leading to mitochondrial respiratory chain impairment. More than 15 individuals affected by variants in NDUFAF5 have been described; however, there is phenotypic heterogeneity within this cohort. Some individuals display features of classical Leigh syndrome with early onset neurodegeneration whereas others live into early adulthood with progressive neurological deficits. Here, we present a clinical report of a 17-year-old African American individual with compound heterozygous mutations in NDUFAF5.The individual presented with childhood onset bilateral optic atrophy and developed progressive neuromuscular decline with relatively preserved cognition over time.

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Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes

Cited by 41 publications

References 31 publications

Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency

Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency

NDUFAF5 variants manifest phenotypically heterogeneously

Case report of atypical Leigh syndrome in an adolescent male with novel biallelic variants in NDUFAF5 and review of the natural history of NDUFAF5‐related disorders

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