Leigh Syndrome: A Tale of Two Genomes.
Ontology highlight
ABSTRACT:
SUBMITTER: Bakare AB
PROVIDER: S-EPMC8385445 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU) deficiency causes an early onset potentially reversible acute liver failure, so far reported in less than 30 patients. We describe two new unrelated patients with an acute liver failure and a neuroimaging compatible with Leigh syndrome (LS) due to TRMU deficiency, a combination not previously reported. Our report enlarges the phenotypical spectrum of TRMU disease.
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Project description:The analysis of transcriptional profiles of cybrid cells harbouring two pathogenic mtDNA variants associated with Leigh syndrome i.e., m.9185T>C in the mt-ATP6 gene and m.13513G>A in the mt-ND5 gene, in comparison to cybrid cells harbouring control mtDNA haplogroups or the wt m.13513G variant.
2023-04-01 | E-MTAB-11035 | biostudies-arrayexpress
Project description:Leigh syndrome is a genetically heterogeneous disorder resulting from deficient oxidative energy biogenesis. The syndrome is characterized by subacute episodic decompensations, transiently elevated lactate, and necrotizing brain lesions most often in the striatum and brainstem. Acute decompensation is often triggered by viral infections. Sequalae from repeated episodes leads to progressive neurological deterioration and death. The severity of Leigh syndrome varies widely, from a rapid demise in childhood to rare adult presentations. Although the causes of Leigh syndrome include genes affecting a variety of different pathways, more than 75 of them are nuclear or mitochondrial encoded genes involved in the assembly and catalytic activity of mitochondrial respiratory complex I. Here we report the detailed clinical and molecular phenotype of two adults with mild presentations of NDUFS3 and NDUFAF6-related Leigh Syndrome. Mitochondrial assays revealed slightly reduced complex I activity in one proband and normal complex I activity in the other. The proband with NDUFS3-related Leigh syndrome was mildly affected and lived into adulthood with novel biallelic variants causing aberrant mRNA splicing (NM_004551.2:c.419G > A; p.Arg140Gln; NM_004551.2:c.381 + 6 T > C). The proband with NDUFAF6-related Leigh syndrome had biallelic variants that cause defects in mRNA splicing (NM_152416.3:c.371 T > C; p.Ile124Thr; NM_152416.3:c.420 + 2_420 + 3insTA). The mild phenotypes of these two individuals may be attributed to some residual production of normal NDUFS3 and NDUFAF6 proteins by NDUFS3 and NDUFAF6 mRNA isoforms alongside mutant transcripts. Taken together, these cases reported herein suggest that splice-regulatory variants to complex I proteins could result in milder phenotypes.
| S-EPMC7749052 | biostudies-literature
Project description:Leigh Syndrome (OMIM 256000) is a heterogeneous neurologic disorder due to damage in mitochondrial energy production that usually starts in early childhood. The first description given by Leigh pointed out neurological symptoms in children under 2 years and premature death. Following cases brought some hypothesis to explain the cause due to similarity to other neurological diseases and led to further investigation for metabolic diseases. Biochemical evaluation and specific metabolic profile suggested impairment in energy production (OXPHOS) in mitochondria. As direct approach to involved tissues is not always possible or safe, molecular analysis is a great cost-effective option and, besides biochemical results, is required to confirm the underlying cause of this syndrome face to clinical suspicion. The Next Generation Sequencing (NGS) advance represented a breakthrough in molecular biology allowing simultaneous gene analysis giving short-time results and increasing the variants underlying this syndrome, counting over 75 monogenic causes related so far. NGS provided confirmation of emerging cases and brought up diagnosis in atypical presentations as late-onset cases, which turned Leigh into a heterogeneous syndrome with variable outcomes. This review highlights clinical presentation in both classic and atypical phenotypes, the investigation pathway throughout confirmation emphasizing the underlying genetic heterogeneity and increasing number of genes assigned to this syndrome as well as available treatment.
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Project description:The insertion and deletion of U residues at specific sites in mRNAs in trypanosome mitochondria is thought to involve 3' terminal uridylyl transferase (TUTase) activity. TUTase activity is also required to create the nonencoded 3' oligo[U] tails of the transacting guide RNAs (gRNAs). We have described two TUTases, RET1 (RNA editing TUTase 1) and RET2 (RNA editing TUTase 2) as components of different editing complexes. Tandem affinity purification-tagged Trypanosoma brucei RET2 (TbRET2) was expressed and localized to the cytosol in Leishmania tarentolae cells by removing the mitochondrial signal sequence. Double-affinity isolation yielded tagged TbRET2, together with a few additional proteins. This material exhibits a U-specific transferase activity in which a single U is added to the 3' end of a single-stranded RNA, thereby confirming that RET2 is a 3' TUTase. We also found that RNA interference of RET2 expression in T. brucei inhibits in vitro U-insertion editing and has no effect on the length of the 3' oligo[U] tails of the gRNAs, whereas down-regulation of RET1 has a minor effect on in vitro U-insertion editing, but produces a decrease in the average length of the oligo[U] tails. This finding suggests that RET2 is responsible for U-insertions at editing sites and RET1 is involved in gRNA 3' end maturation, which is essential for creating functional gRNAs. From these results we have functionally relabeled the previously described TUT-II complex containing RET1 as the guide RNA processing complex.
| S-EPMC196853 | biostudies-other
Project description:As a result of a founder effect, a Leigh syndrome variant called Leigh syndrome, French-Canadian type (LSFC, MIM / 220,111) is more frequent in Saguenay-Lac-Saint-Jean (SLSJ), a geographically isolated region on northeastern Quebec, Canada. LSFC is a rare autosomal recessive mitochondrial neurodegenerative disorder due to damage in mitochondrial energy production. LSFC is caused by pathogenic variants in the nuclear gene leucine-rich pentatricopeptide repeat-containing (LRPPRC). Despite progress understanding the molecular mode of action of LRPPRC gene, there is no treatment for this disease. The present study aims to identify the biological pathways altered in the LSFC disorder through microarray-based transcriptomic profile analysis of twelve LSFC cell lines compared to twelve healthy ones, followed by gene ontology (GO) and pathway analyses. A set of 84 significantly differentially expressed genes were obtained (p ≥ 0.05; Fold change (Flc) ≥ 1.5). 45 genes were more expressed (53.57%) in LSFC cell lines compared to controls and 39 (46.43%) had lower expression levels. Gene ontology analysis highlighted altered expression of genes involved in the mitochondrial respiratory chain and energy production, glucose and lipids metabolism, oncogenesis, inflammation and immune response, cell growth and apoptosis, transcription, and signal transduction. Considering the metabolic nature of LSFC disease, genes included in the mitochondrial respiratory chain and energy production cluster stood out as the most important ones to be involved in LSFC mitochondrial disorder. In addition, the protein-protein interaction network indicated a strong interaction between the genes included in this cluster. The mitochondrial gene NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), with higher expression in LSFC cells, represents a target for functional studies to explain the role of this gene in LSFC disease. This work provides, for the first time, the LSFC gene expression profile in fibroblasts isolated from affected individuals. This represents a valuable resource to understand the pathogenic basis and consequences of LRPPRC dysfunction.
| S-EPMC8856909 | biostudies-literature
Project description:Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar, severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with markedly reduced amounts of peripheral stalk proteins, and complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-∆ex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.
| S-EPMC9474623 | biostudies-literature
Project description:Methane monooxygenase (MMO) enzymes activate O2 for oxidation of methane. Two distinct MMOs exist in nature, a soluble form that uses a diiron active site (sMMO) and a membrane-bound form with a catalytic copper center (pMMO). Understanding the reaction mechanisms of these enzymes is of fundamental importance to biologists and chemists, and is also relevant to the development of new biocatalysts. The sMMO catalytic cycle has been elucidated in detail, including O2 activation intermediates and the nature of the methane-oxidizing species. By contrast, many aspects of pMMO catalysis remain unclear, most notably the nuclearity and molecular details of the copper active site. Here, we review the current state of knowledge for both enzymes, and consider pMMO O2 activation intermediates suggested by computational and synthetic studies in the context of existing biochemical data. Further work is needed on all fronts, with the ultimate goal of understanding how these two remarkable enzymes catalyze a reaction not readily achieved by any other metalloenzyme or biomimetic compound.
| S-EPMC5352483 | biostudies-literature
Project description:Background: Leigh syndrome (LS) is the most common pediatric mitochondrial diseases caused by MRC defect. LS patients typically have onset age before 2 years old and have various clinical features. The purpose of this study was to evaluate the various characteristics between the group that were early onset and late onset patients. Methods: The medical records of this study used records between 2006 and 2017 (N = 110). Clinical characteristics, diagnostic evaluations, and neuro image studying of LS were reviewed in our study. We statistically analyzed data from patients diagnosed with LS at our hospital by using subgroup analysis was performed to divide patients according to the onset age. Results: Among the patients, 89 patients (80.9%) had the onset age before 2 years old, and 21 patents (19.1%) had onset age after 2 years old. In subgroup analysis first clinical presentation age, diagnosis age and several onset symptoms in the clinical characteristics were statistically significant. Early onset age group showed delayed development and late onset age group showed motor weakness and ataxia. However, Diagnostics evaluation and MRI findings showed no significant differences. The clinical status monitored during the last visit showed statistically significant differences in the clinical severity. In the early onset age group clinical status was more severe than late onset age group. Conclusions: Although the onset of Leigh syndrome is known to be under 2 years, there are many late onset cases were existed more than expected. Early onset LS patients have poor prognosis compare with late onset LS patients. Therefore, the specific phenotype according to the age of onset should be well-observed. Onset of LS is important in predicting clinical severity or prognosis, and it is necessary to provide individualized treatment or follow-up protocols for each patient.
| S-EPMC7174756 | biostudies-literature
Project description:BackgroundLeigh syndrome is a neurodegenerative disorder caused by mitochondrial dysfunction with both phenotypic and genetic heterogeneity. Mitochondrial impairments are usually demonstrated by skeletal muscle biopsy. We report a case of Leigh syndrome diagnosed by endomyocardial biopsy (EMB), not by skeletal muscle biopsy.Case summaryAt aged 7 months, the patient had delayed motor development. He developed metabolic acidosis triggered by an infection with elevated lactate and pyruvate values in serum and cerebrospinal fluid when he was 1 year old. T2-weighted imaging on magnetic resonance imaging of the brain revealed bilateral hyperintensity in midbrain and dorsal pons. Biopsied skeletal muscle did not show evidence of mitochondrial disease. Left ventricular hypertrophy, bilateral putamen hyperintensity in T2-weighted imaging and a lactate peak in the right basal ganglia in single voxel spectroscopy, and a convulsive seizure appeared at the age of 12, 15, and 16, respectively. When he was 17 years old, biopsied myocardium showed cytoplasmic vacuolization and a marked proliferation of mitochondria within myofibrils pathologically. Respiratory chain enzyme activity of the biopsied myocardium showed decreased activity of complex I. Genetic testing revealed an m.14453 A>G mutation on the MT-ND6 gene. He was finally diagnosed with Leigh syndrome. Administration of oral 5-aminolevulinic acid reduced the frequency of seizures.DiscussionEMB led to the diagnosis of Leigh syndrome. Efforts to find and conduct the biopsy of affected organs are important to diagnose mitochondrial disease. EMB is a useful diagnostic method when there is a difficulty in diagnosing mitochondrial disease by skeletal muscle biopsy.
| S-EPMC7898571 | biostudies-literature