Human Mutation · 2013 · 86 citations · open access
<i>MTO1</i> Mutations are Associated with Hypertrophic Cardiomyopathy and Lactic Acidosis and Cause Respiratory Chain Deficiency in Humans and Yeast
AbstractWe report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.
https://doi.org/10.1002/humu.22393Molecular Genetics and Metabolism · 2017 · 38 citations · open access
The genotypic and phenotypic spectrum of MTO1 deficiency
AbstractBACKGROUND: Mitochondrial diseases, a group of multi-systemic disorders often characterized by tissue-specific phenotypes, are usually progressive and fatal disorders resulting from defects in oxidative phosphorylation. MTO1 (Mitochondrial tRNA Translation Optimization 1), an evolutionarily conserved protein expressed in high-energy demand tissues has been linked to human early-onset combined oxidative phosphorylation deficiency associated with hypertrophic cardiomyopathy, often referred to as combined oxidative phosphorylation deficiency-10 (COXPD10). MATERIAL AND METHODS: Thirty five cases of MTO1 deficiency were identified and reviewed through international collaboration. The cases of two female siblings, who presented at 1 and 2years of life with seizures, global developmental delay, hypotonia, elevated lactate and complex I and IV deficiency on muscle biopsy but without cardiomyopathy, are presented in detail. RESULTS: For the description of phenotypic features, the denominator varies as the literature was insufficient to allow for complete ascertainment of all data for the 35 cases. An extensive review of all known MTO1 deficiency cases revealed the most common features at presentation to be lactic acidosis (LA) (21/34; 62% cases) and hypertrophic cardiomyopathy (15/34; 44% cases). Eventually lactic acidosis and hypertrophic cardiomyopathy are described in 35/35 (100%) and 27/34 (79%) of patients with MTO1 deficiency, respectively; with global developmental delay/intellectual disability present in 28/29 (97%), feeding difficulties in 17/35 (49%), failure to thrive in 12/35 (34%), seizures in 12/35 (34%), optic atrophy in 11/21 (52%) and ataxia in 7/34 (21%). There are 19 different pathogenic MTO1 variants identified in these 35 cases: one splice-site, 3 frameshift and 15 missense variants. None have bi-allelic variants that completely inactivate MTO1; however, patients where one variant is truncating (i.e. frameshift) while the second one is a missense appear to have a more severe, even fatal, phenotype. These data suggest that complete loss of MTO1 is not viable. A ketogenic diet may have exerted a favourable effect on seizures in 2/5 patients. CONCLUSION: MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Although subjective clinical improvement was observed in a small number of patients on therapies such as ketogenic diet and dichloroacetate, no evidence-based effective therapy exists.
https://doi.org/10.1016/j.ymgme.2017.11.003Journal of Neuro-Ophthalmology · 2019 · 3 citations
Novel Mitochondrial Translation Optimizer-1 Mutations as a Cause of Hereditary Optic Neuropathy
AbstractMitochondrial diseases encompass a wide spectrum of inherited disorders associated with dysfunction of mitochondrial oxidative phosphorylation. They can arise at any age and can involve virtually any organ system, often leading to multisystem presentations (1). The birth prevalence is 6.2 in 100,000 and significantly higher in consanguineous communities (2). Mitochondrial diseases have been ascribed to numerous mutations both in nuclear and mitochondrial DNA. Mitochondrial tRNA translation optimization 1 (MTO1) gene is a nuclear gene required for mitochondrial protein translation. Biallelic mutations in this gene were initially described in 2012 in patients with infantile-onset cardiomyopathy and lactic acidosis (3). Since then, 35 patients from 27 unrelated families have been reported (4–11). Of these, 11 cases (31%) were associated with optic neuropathy (4,5,7,9,10). We report 2 novel MTO1 mutations, one of which is the first nonsense MTO1 mutation known to cause human disease, associated with hereditary optic neuropathy in our patient but not in his brother, who had the same mutations. A 17-year-old boy with an extensive systemic medical history presented with bilateral painless, progressive visual decline over the preceding several months causing difficulty with seeing the blackboard, reading, and writing at school. Concurrently, his parents noted associated decline in cognitive function. His medical history was notable for cardiomyopathy characterized by left ventricular hypertrophy and pulmonary stenosis diagnosed at 2 weeks of age; developmental delay with acquisition of sitting at 9 months, ability to walk independently at 19 months, and delayed speech; failure to thrive in infancy; and exercise intolerance and anxiety during childhood. At age 17, he had his first generalized seizure, which responded to treatment and has remained stable. An ophthalmic examination at age 12 showed a baseline visual acuity of 20/20 and no abnormal findings in both eyes. He did not use alcohol, tobacco, or illicit drugs. Treatment included ascorbic acid, vitamin B complex, multivitamin, ubidecarenone (coenzyme Q10), levocarnitine, and lamotrigine. He had a 19-year-old brother with a similar but milder phenotype characterized by congenital cardiac defects, developmental delay, epilepsy, and milder intellectual disability, but no vision loss. His parents were in good general health without eye problems. At the time of presentation, the patient's neurological examination showed impaired memory, sparse speech, hypotonia, and brisk tendon reflexes. His visual acuities were 20/400 on the right and 20/200 on the left. Examination was remarkable for optic nerve temporal pallor and circumpapillary telangiectasias in both eyes (Fig. 1A, B). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) demonstrated bilateral temporal thinning (Fig. 2A). Serologic testing for sarcoidosis, Lyme antibodies, and aquaporin-4 antibodies, MRI of the brain with and without contrast, and cerebrospinal fluid analysis were all negative. Blood lactate was elevated (4.6 mmol/L, normal <2 mmol/L). Skeletal muscle histology was unremarkable. Respiratory chain enzyme activities (RCA) in skin-derived fibroblasts from the proband and the brother assessed as previously described (12) showed combined deficiencies and elevation of citrate synthase, a marker of mitochondrial mass (Table 1). Genetic evaluation for Leber hereditary optic neuropathy (LHON) commonly associated mutations m.11778 G > A, m.14484T > C, and m.3460 G > A was negative (13). Whole exome sequencing revealed the presence of 2 novel heterozygous mutations in MTO1 gene (ENST00000498286): p.R484W and p.R488*. The missense mutation was predicted to be pathogenic by in-silico analyses (PROVEAN, SIFT, and PolyPhen-2) (14,15). The brothers carried both mutations, and each parent carried one of the mutant alleles. The patient was counseled to refrain from alcohol and tobacco use and started on an empiric trial of nicotinamide riboside, an oral precursor to vitamin B3 and nicotinamide adenine dinucleotide, shown to induce mitochondrial biogenesis in cellular and animal models, and used experimentally in the treatment of mitochondrial myopathy and fatty liver disease (16,17). At the last follow-up 2 years after the initial presentation, he had continued bilateral vision loss to hand motion, temporal optic nerve pallor, and stabilized RNFL thinning on OCT (Fig. 2B). His neurological examination was stable as well as his cardiomyopathy.FIG. 1.: Color photographs of the optic nerve in the (A) right eye and (B) left eye. There is demonstration of normal macula, temporal optic nerve pallor, and circumpapillary telangiectasias bilaterally.FIG. 2.: Optical coherence tomography of the retinal nerve fiber layer (A) at presentation and (B) at 2 years of follow-up showing bilateral temporal thinning.TABLE 1.: Respiratory chain enzyme activities normalized to citrate synthaseWe describe a complex case of developmental delay, hypertrophic cardiomyopathy, intellectual disability, epilepsy, and hereditary optic neuropathy secondary to compound heterozygous novel mutations in MTO1 gene. Mutations in this gene have variable phenotypic expression, including optic neuropathy. Before this report, only 35 patients, from 27 unrelated families, had been described (3–11). The broad phenotypic spectrum encompasses a neonatal onset form, which is usually rapidly progressive and often fatal, and a late-onset slowly progressive or stable form. Early onset is usually associated with unfavorable prognosis (10). Hallmark features include cardiomyopathy, lactic acidosis, and cognitive disability (10). Optic neuropathy has been reported in the minority of patients (11/35 [31%]) with biallelic MTO1 mutations (Table 2) (4,5,7,9,10). These reported cases showed no strong sex predilection with optic atrophy occurring by adolescence or early adulthood. Reported visual acuity ranged from 20/20 to 20/200 bilaterally. All patients displayed bilateral optic atrophy with or without demonstration of RNFL thinning on OCT (4,5,7,9,10). Visual-evoked potential, when reported, had reduced P100 amplitude and varying latency (4,5,7,10). The genotype–phenotype relationship is not well delineated. It was hypothesized that the presence of a frameshift variant might be associated with an early neonatal presentation and a more severe prognosis and that a truncating mutation might not be compatible with survival (10). We describe for the first time a nonsense mutation associated with human disease; our proband with MTO1 mutations presented with late-onset and less severe phenotype than many reported cases, thus demonstrating that a truncating allele does not cause prenatal lethality. Moreover, the proband's brother had identical mutations but did not have any visual problems and had a milder disease course. The only published cases of MTO1-related optic neuropathy with significant family history are 2 related siblings with the p.R504C homozygous mutation. The ophthalmic disease severity differed among the 2 siblings—one had visual acuities of 20/100 in the right eye and 20/70 in the left eye, whereas the other had 20/20 vision bilaterally (7).TABLE 2.: Published cases of optic neuropathy in patients with at least one identified MTO1 mutationDiagnosis was achieved by whole exome sequencing but suspected on the basis of the clinical phenotype and elevated lactate, which has been reported in all patients with MTO1 mutations. Pathogenicity was confirmed by detecting impaired RCAs in fibroblasts. Decreased RCAs in skin-derived fibroblasts have been reported in 7/11 patients and represent an additional diagnostic tool (10,11). In conclusion, optic neuropathy is an uncommon manifestation of MTO1 mitochondrial disease and can resemble LHON. Genetic evaluation for MTO1 mutations is indicated in patients who test negative for mitochondrial DNA mutations and display systemic manifestations of mitochondrial disease, such as cardiomyopathy, lactic acidosis, and developmental delay/cognitive dysfunction. RCA assessment can be useful, but a negative result does not exclude the diagnosis. Genotype–phenotype correlations are complex and not completely understood. Intrafamilial variability in clinical presentation and severity make prognosis challenging. Better characterization of MTO1 diseases is warranted to facilitate awareness, diagnosis, and potential therapeutic development. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser; b. Acquisition of data: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser; c. Analysis and interpretation of data: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser. Category 2: a. Drafting the manuscript: E. Li, V. Emmanuele, F. Testa, M. Hirano, and R. Lesser; b. Revising it for intellectual content: E. Li, V. Emmanuele, F. Testa, M. Hirano, and R. Lesser. Category 3: a. Final approval of the completed manuscript: E. Li, V. Emmanuele, F. Testa, C. D. A. M. Moreno, M. Hirano, and R. Lesser.
https://doi.org/10.1097/wno.0000000000000858Greater South Information System · 2018 · 0 citations · open access
Defects in the mitochondrial-tRNA modification enzymes MTO1 and GTPBP3 promote different metabolic reprogramming through a HIF-PPARγ-UCP2-AMPK axis
AbstractHuman proteins MTO1 and GTPBP3 are thought to jointly catalyze the modification of the wobble uridine in mitochondrial tRNAs. Defects in each protein cause infantile hypertrophic cardiomyopathy with lactic acidosis. However, the underlying mechanisms are mostly unknown. Using fibroblasts from an MTO1 patient and MTO1 silenced cells, we found that the MTO1 deficiency is associated with a metabolic reprogramming mediated by inactivation of AMPK, down regulation of the uncoupling protein 2 (UCP2) and transcription factor PPARγ, and activation of the hypoxia inducible factor 1 (HIF-1). As a result, glycolysis and oxidative phosphorylation are uncoupled, while fatty acid metabolism is altered, leading to accumulation of lipid droplets in MTO1 fibroblasts. Unexpectedly, this response is different from that triggered by the GTPBP3 defect, as GTPBP3-depleted cells exhibit AMPK activation, increased levels of UCP2 and PPARγ, and inactivation of HIF-1. In addition, fatty acid oxidation and respiration are stimulated in these cells. Therefore, the HIF-PPARγ-UCP2-AMPK axis is operating differently in MTO1- and GTPBP3-defective cells, which strongly suggests that one of these proteins has an additional role, besides mitochondrial-tRNA modification. This work provides new and useful information on the molecular basis of the MTO1 and GTPBP3 defects and on putative targets for therapeutic intervention.
https://doi.org/10.60692/8yhsw-2b086