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1.
PLoS One ; 14(8): e0220706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393920

RESUMO

Fetida Cave is an active sulfuric acid cave influenced by seawater, showing abundant microbial communities that organize themselves under three main different morphologies: water filaments, vermiculations and moonmilk deposits. These biofilms/deposits have different cave distribution, pH, macro- and microelement and mineralogical composition, carbon and nitrogen content. In particular, water filaments and vermiculations had circumneutral and slightly acidic pH, respectively, both had abundant organic carbon and high microbial diversity. They were rich in macro- and microelements, deriving from mineral dissolution, and, in the case of water filaments, from seawater composition. Vermiculations had different color, partly associated with their mineralogy, and unusual minerals probably due to trapping capacities. Moonmilk was composed of gypsum, poor in organic matter, had an extremely low pH (0-1) and low microbial diversity. Based on 16S rRNA gene analysis, the microbial composition of the biofilms/deposits included autotrophic taxa associated with sulfur and nitrogen cycles and biomineralization processes. In particular, water filaments communities were characterized by bacterial taxa involved in sulfur oxidation and reduction in aquatic, aphotic, microaerophilic/anoxic environments (Campylobacterales, Thiotrichales, Arenicellales, Desulfobacterales, Desulforomonadales) and in chemolithotrophy in marine habitats (Oceanospirillales, Chromatiales). Their biodiversity was linked to the morphology of the water filaments and their collection site. Microbial communities within vermiculations were partly related to their color and showed high abundance of unclassified Betaproteobacteria and sulfur-oxidizing Hydrogenophilales (including Sulfuriferula), and Acidiferrobacterales (including Sulfurifustis), sulfur-reducing Desulfurellales, and ammonia-oxidizing Planctomycetes and Nitrospirae. The microbial community associated with gypsum moonmilk showed the strong dominance (>60%) of the archaeal genus Thermoplasma and lower abundance of chemolithotrophic Acidithiobacillus, metal-oxidizing Metallibacterium, Sulfobacillus, and Acidibacillus. This study describes the geomicrobiology of water filaments, vermiculations and gypsum moonmilk from Fetida Cave, providing insights into the microbial taxa that characterize each morphology and contribute to biogeochemical cycles and speleogenesis of this peculiar seawater-influenced sulfuric acid cave.

2.
Acta Neurol Scand ; 140(3): 184-193, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102535

RESUMO

OBJECTIVES: To determine the prevalence of epilepsy in children with early-onset mitochondrial diseases (MDs) and to evaluate the epileptic phenotypes and associated features. MATERIALS AND METHODS: Children affected by MD with onset during the first year of life were enrolled. Patients were classified according to their mitochondrial phenotype, and all findings in patients with epilepsy versus patients without were compared. The epileptic features were analyzed. RESULTS: The series includes 129 patients (70 females) with median age at disease onset of 3 months. The median time of follow-up was 5 years. Non-syndromic mitochondrial encephalopathy and pyruvate dehydrogenase complex deficiency were the main mitochondrial diseases associated with epilepsy (P < 0.05). Seizures occurred in 48%, and the presence of epilepsy was significantly associated with earlier age at disease onset, presence of perinatal manifestations, and early detection of developmental delay and regression (P < 0.001). Epileptic encephalopathy (EE) with spasms and EE with prominent focal seizures were the most detected epileptic syndromes (37% and 27.4%). Several seizure types were recorded in 53.2%, with the unusual association of generalized and focal epileptic pattern. Disabling epilepsy was detected in 63% and was associated with early seizure onset, presence of several seizure types, epileptic syndrome featuring EE, and the recurrence of episodes of status epilepticus and epilepsia partialis continua (P < 0.05). CONCLUSIONS: Epilepsy in children with early-onset MD may be a presenting or a prominent symptom in a multisystemic clinical presentation. Epilepsy-related factors could determine a worst seizure outcome, leading to a more severe burned of the disease.

3.
Hum Mutat ; 40(10): 1731-1748, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31045291

RESUMO

Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3' ends of mitochondrial pre-tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile-onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism.

6.
Dis Model Mech ; 12(3)2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30833296

RESUMO

Mitochondrial DNA depletion syndromes (MDS) are a group of rare autosomal recessive disorders with early onset and no cure available. MDS are caused by mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance, and characterized by both a strong reduction in mtDNA content and severe mitochondrial defects in affected tissues. Mutations in MPV17, a nuclear gene encoding a mitochondrial inner membrane protein, have been associated with hepatocerebral forms of MDS. The zebrafish mpv17 null mutant lacks the guanine-based reflective skin cells named iridophores and represents a promising model to clarify the role of Mpv17. In this study, we characterized the mitochondrial phenotype of mpv17-/- larvae and found early and severe ultrastructural alterations in liver mitochondria, as well as significant impairment of the respiratory chain, leading to activation of the mitochondrial quality control. Our results provide evidence for zebrafish Mpv17 being essential for maintaining mitochondrial structure and functionality, while its effects on mtDNA copy number seem to be subordinate. Considering that a role in nucleotide availability had already been postulated for MPV17, that embryos blocked in pyrimidine synthesis do phenocopy mpv17-/- knockouts (KOs) and that mpv17-/- KOs have impaired Dihydroorotate dehydrogenase activity, we provided mpv17 mutants with the pyrimidine precursor orotic acid (OA). Treatment with OA, an easily available food supplement, significantly increased both iridophore number and mtDNA content in mpv17 -/- mutants, thus linking the loss of Mpv17 to pyrimidine de novo synthesis and opening a new simple therapeutic approach for MPV17-related MDS.


Assuntos
Pleiotropia Genética , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Homologia de Sequência de Aminoácidos , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Vias Biossintéticas , DNA Mitocondrial/genética , Transporte de Elétrons , Dosagem de Genes , Humanos , Larva/genética , Larva/metabolismo , Fígado/metabolismo , Proteínas de Membrana/genética , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/genética , Mutação/genética , Nucleotídeos/metabolismo , Fenótipo , Pirimidinas/biossíntese , Estresse Fisiológico , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
7.
Hum Mutat ; 40(5): 601-618, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801875

RESUMO

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.

8.
Am J Med Genet A ; 179(5): 827-831, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30773800

RESUMO

Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes.

9.
EMBO Mol Med ; 11(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30552096

RESUMO

Loss-of-function mutations in APOPT1, a gene exclusively found in higher eukaryotes, cause a characteristic type of cavitating leukoencephalopathy associated with mitochondrial cytochrome c oxidase (COX) deficiency. Although the genetic association of APOPT1 pathogenic variants with isolated COX defects is now clear, the biochemical link between APOPT1 function and COX has remained elusive. We investigated the molecular role of APOPT1 using different approaches. First, we generated an Apopt1 knockout mouse model which shows impaired motor skills, e.g., decreased motor coordination and endurance, associated with reduced COX activity and levels in multiple tissues. In addition, by achieving stable expression of wild-type APOPT1 in control and patient-derived cultured cells we ruled out a role of this protein in apoptosis and established instead that this protein is necessary for proper COX assembly and function. On the other hand, APOPT1 steady-state levels were shown to be controlled by the ubiquitination-proteasome system (UPS). Conversely, in conditions of increased oxidative stress, APOPT1 is stabilized, increasing its mature intramitochondrial form and thereby protecting COX from oxidatively induced degradation.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Proteínas Mitocondriais/metabolismo , Multimerização Proteica , Espécies Reativas de Oxigênio/metabolismo , Resposta a Proteínas não Dobradas , Animais , Proteínas Reguladoras de Apoptose/deficiência , Células Cultivadas , Teste de Complementação Genética , Humanos , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/deficiência
10.
Sci Rep ; 8(1): 17569, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514906

RESUMO

Chemical mobility of crystalline and amorphous SiO2 plays a fundamental role in several geochemical and biological processes, with silicate minerals being the most abundant components of the Earth's crust. Although the oldest evidences of life on Earth are fossilized in microcrystalline silica deposits, little is known about the functional role that bacteria can exert on silica mobility at non-thermal and neutral pH conditions. Here, a microbial influence on silica mobilization event occurring in the Earth's largest orthoquartzite cave is described. Transition from the pristine orthoquartzite to amorphous silica opaline precipitates in the form of stromatolite-like structures is documented through mineralogical, microscopic and geochemical analyses showing an increase of metals and other bioessential elements accompanied by permineralized bacterial cells and ultrastructures. Illumina sequencing of the 16S rRNA gene describes the bacterial diversity characterizing the consecutive amorphization steps to provide clues on the biogeochemical factors playing a role in the silica solubilization and precipitation processes. These results show that both quartz weathering and silica mobility are affected by chemotrophic bacterial communities, providing insights for the understanding of the silica cycle in the subsurface.

11.
Hum Mutat ; 39(12): 2060-2071, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30252181

RESUMO

Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients' cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects.

12.
EMBO Mol Med ; 10(10)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30190335

RESUMO

TIMM50 is an essential component of the TIM23 complex, the mitochondrial inner membrane machinery that imports cytosolic proteins containing a mitochondrial targeting presequence into the mitochondrial inner compartment. Whole exome sequencing (WES) identified compound heterozygous pathogenic mutations in TIMM50 in an infant patient with rapidly progressive, severe encephalopathy. Patient fibroblasts presented low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential, and impaired TIM23-dependent protein import. As a consequence, steady-state levels of several components of mitochondrial respiratory chain were decreased, resulting in decreased respiration and increased ROS production. Growth of patient fibroblasts in galactose shifted energy production metabolism toward oxidative phosphorylation (OxPhos), producing an apparent improvement in most of the above features but also increased apoptosis. Complementation of patient fibroblasts with TIMM50 improved or restored these features to control levels. Moreover, RNASEH1 and ISCU mutant fibroblasts only shared a few of these features with TIMM50 mutant fibroblasts. Our results indicate that mutations in TIMM50 cause multiple mitochondrial bioenergetic dysfunction and that functional TIMM50 is essential for cell survival in OxPhos-dependent conditions.

13.
Orphanet J Rare Dis ; 13(1): 120, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025539

RESUMO

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.

14.
Essays Biochem ; 62(3): 271-286, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-30030362

RESUMO

The structural biogenesis and functional proficiency of the multiheteromeric complexes forming the mitochondrial oxidative phosphorylation system (OXPHOS) require the concerted action of a number of chaperones and other assembly factors, most of which are specific for each complex. Mutations in a large number of these assembly factors are responsible for mitochondrial disorders, in most cases of infantile onset, typically characterized by biochemical defects of single specific complexes. In fact, pathogenic mutations in complex-specific assembly factors outnumber, in many cases, the repertoire of mutations found in structural subunits of specific complexes. The identification of patients with specific defects in assembly factors has provided an important contribution to the nosological characterization of mitochondrial disorders, and has also been a crucial means to identify a huge number of these proteins in humans, which play an essential role in mitochondrial bioenergetics. The wide use of next generation sequencing (NGS) has led to and will allow the identifcation of additional components of the assembly machinery of individual complexes, mutations of which are responsible for human disorders. The functional studies on patients' specimens, together with the creation and characterization of in vivo models, are fundamental to better understand the mechanisms of each of them. A new chapter in this field will be, in the near future, the discovery of mechanisms and actions underlying the formation of supercomplexes, molecular structures formed by the physical, and possibly functional, interaction of some of the individual respiratory complexes, particularly complex I (CI), III (CIII), and IV (CIV).

15.
Orphanet J Rare Dis ; 13(1): 45, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29615062

RESUMO

BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

16.
Eur J Med Genet ; 61(10): 581-584, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29621620

RESUMO

Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain-lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations.

17.
J Hum Genet ; 63(5): 563-568, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29531337

RESUMO

Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.


Assuntos
Heterozigoto , Íntrons , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Mutação de Sentido Incorreto , RNA Mensageiro/genética , Sequenciamento Completo do Exoma , Alelos , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Haplótipos , Humanos , Lactente , Linfócitos/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Proteínas Mitocondriais , Linhagem , Fenótipo
18.
Hum Mutat ; 39(4): 563-578, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29314548

RESUMO

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

19.
Metab Brain Dis ; 33(3): 805-812, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29359243

RESUMO

A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies.

20.
Hum Mol Genet ; 27(3): 499-504, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29211846

RESUMO

Mitochondrial diseases are a plethora of inherited neuromuscular disorders sharing defects in mitochondrial respiration, but largely different from one another for genetic basis and pathogenic mechanism. Whole exome sequencing was performed in a familiar trio (trio-WES) with a child affected by severe epileptic encephalopathy associated with respiratory complex I deficiency and mitochondrial DNA depletion in skeletal muscle. By trio-WES we identified biallelic mutations in SLC25A10, a nuclear gene encoding a member of the mitochondrial carrier family. Genetic and functional analyses conducted on patient fibroblasts showed that SLC25A10 mutations are associated with reduction in RNA quantity and aberrant RNA splicing, and to absence of SLC25A10 protein and its transporting function. The yeast SLC25A10 ortholog knockout strain showed defects in mitochondrial respiration and mitochondrial DNA content, similarly to what observed in the patient skeletal muscle, and growth susceptibility to oxidative stress. Albeit patient fibroblasts were depleted in the main antioxidant molecules NADPH and glutathione, transport assays demonstrated that SLC25A10 is unable to transport glutathione. Here, we report the first recessive mutations of SLC25A10 associated to an inherited severe mitochondrial neurodegenerative disorder. We propose that SLC25A10 loss-of-function causes pathological disarrangements in respiratory-demanding conditions and oxidative stress vulnerability.

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