Leigh Syndrome Due to mtDNA Pathogenic Variants

Pereira, Cristina; Souza, Carolina F. de; Vedolin, Leonardo; Vairo, Filippo Pinto e; Lorea, Cláudia Fernandes; Sobreira, Cláudia Ferreira da Rosa; Nogueira, Célia; Vilarinho, Laura

doi:10.1590/2326-4594-jiems-2018-0003

Cited by 6 publications

(4 citation statements)

References 41 publications

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“…These findings, the in silico predictions, the frequency of 0.002% in the MITOMAP database, and the conservation of this locus are in favor of a pathogenic status (Ogawa et al, 2017). The m.6547T>C variant identified in P110, first described by Yoneda in 1990 and later reported by our group (Pereira et al, 2019), was recently reclassified by the new version of APOGEE (APG2) as likely pathogenic.…”

Section: Pathogenic/likely Pathogenic Variantsmentioning

confidence: 70%

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

Nogueira,

Pereira,

Silva

et al. 2024

Front. Cell Dev. Biol.

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Introduction: Rare disorders that are genetically and clinically heterogeneous, such as mitochondrial diseases (MDs), have a challenging diagnosis. Nuclear genes codify most proteins involved in mitochondrial biogenesis, despite all mitochondria having their own DNA. The development of next-generation sequencing (NGS) technologies has revolutionized the understanding of many genes involved in the pathogenesis of MDs. In this new genetic era, using the NGS approach, we aimed to identify the genetic etiology for a suspected MD in a cohort of 450 Portuguese patients.Methods: We examined 450 patients using a combined NGS strategy, starting with the analysis of a targeted mitochondrial panel of 213 nuclear genes, and then proceeding to analyze the whole mitochondrial DNA.Results and Discussion: In this study, we identified disease-related variants in 134 (30%) analyzed patients, 88 with nuclear DNA (nDNA) and 46 with mitochondrial DNA (mtDNA) variants, most of them being pediatric patients (66%), of which 77% were identified in nDNA and 23% in mtDNA. The molecular analysis of this cohort revealed 72 already described pathogenic and 20 novel, probably pathogenic, variants, as well as 62 variants of unknown significance. For this cohort of patients with suspected MDs, the use of a customized gene panel provided a molecular diagnosis in a timely and cost-effective manner. Patients who cannot be diagnosed after this initial approach will be further selected for whole-exome sequencing.Conclusion: As a national laboratory for the study and research of MDs, we demonstrated the power of NGS to achieve a molecular etiology, expanding the mutational spectrum and proposing accurate genetic counseling in this group of heterogeneous diseases without therapeutic options.

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Section: Pathogenic/likely Pathogenic Variantsmentioning

confidence: 70%

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

Nogueira,

Pereira,

Silva

et al. 2024

Front. Cell Dev. Biol.

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“…P24 and P25 presented m.13513G>A (p.Asp393Asn), a mutation that has already been outlined by Ruiter et al in a patient with CI deficiency, cardiac rhythm perturbation, and optic atrophy [ 62 ], with our patients presenting cardiomyopathy and hypotonia, and ataxia and apnea, respectively. Our cohort also includes a patient with m.4142G>T (p.Arg279Leu) in MT-ND1 (P26 [ 30 ]) and another one with m.6547T>C in MT-CO1 (P27 [ 30 ]).…”

Section: Discussionmentioning

confidence: 99%

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

Baldo

Nogueira

Pereira

et al. 2023

Genes

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Mitochondrial diseases are the most common inherited inborn error of metabolism resulting in deficient ATP generation, due to failure in homeostasis and proper bioenergetics. The most frequent mitochondrial disease manifestation in children is Leigh syndrome (LS), encompassing clinical, neuroradiological, biochemical, and molecular features. It typically affects infants but occurs anytime in life. Considering recent updates, LS clinical presentation has been stretched, and is now named LS spectrum (LSS), including classical LS and Leigh-like presentations. Apart from clinical diagnosis challenges, the molecular characterization also progressed from Sanger techniques to NGS (next-generation sequencing), encompassing analysis of nuclear (nDNA) and mitochondrial DNA (mtDNA). This upgrade resumed steps and favored diagnosis. Hereby, our paper presents molecular and clinical data on a Portuguese cohort of 40 positive cases of LSS. A total of 28 patients presented mutation in mtDNA and 12 in nDNA, with novel mutations identified in a heterogeneous group of genes. The present results contribute to the better knowledge of the molecular basis of LS and expand the clinical spectrum associated with this syndrome.

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“…It was revised from a "Variant of Uncertain Significance" to "Likely Pathogenic" in a recent evaluation [18]. A related mutation, ND1_R279L, was discovered in a four-year-old with Leigh Syndrome, with reduced Complex I activity [66]. In E. coli, the alanine substitution had a similar activity to the glutamine, 55%, suggesting that the loss of the original arginine was key.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Human Clinical Mutations of Mitochondrial ND1 in a Bacterial Model System for Complex I

Alkhaldi

Phan

Vik

2022

Life

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The most common causes of mitochondrial dysfunction and disease include mutations in subunits and assembly factors of Complex I. Numerous mutations in the mitochondrial gene ND1 have been identified in humans. Currently, a bacterial model system provides the only method for rapid construction and analysis of mutations in homologs of human ND1. In this report, we have identified nine mutations in human ND1 that are reported to be pathogenic and are located at subunit interfaces. Our hypothesis was that these mutations would disrupt Complex I assembly. Seventeen mutations were constructed in the homologous nuoH gene in an E. coli model system. In addition to the clinical mutations, alanine substitutions were constructed in order to distinguish between a deleterious effect from the introduction of the mutant residue and the loss of the original residue. The mutations were moved to an expression vector containing all thirteen genes of the E. coli nuo operon coding for Complex I. Membrane vesicles were prepared and rates of deamino-NADH oxidase activity and proton translocation were measured. Samples were also tested for assembly by native gel electrophoresis and for expression of NuoH by immunoblotting. A range of outcomes was observed: Mutations at four of the sites allow normal assembly with moderate activity (50–76% of wild type). Mutations at the other sites disrupt assembly and/or activity, and in some cases the outcomes depend upon the amino acid introduced. In general, the outcomes are consistent with the proposed pathogenicity in humans.

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Leigh Syndrome Due to mtDNA Pathogenic Variants

Cited by 6 publications

References 41 publications

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

The genetic landscape of mitochondrial diseases in the next-generation sequencing era: a Portuguese cohort study

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

Analysis of Human Clinical Mutations of Mitochondrial ND1 in a Bacterial Model System for Complex I

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