Karine Auré

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (20)86.73 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We describe four patients from three independent families with the m.1644G > A in the MT-TV gene, previously reported without demonstration of its deleterious impact. Very high mutation proportion co-segregated with cytochrome oxidase defect in single muscle fibers and respiratory defect and in cybrids as shown by spectrophotometric assays and polarography. The mutation appeared to have a very steep threshold effect with asymptomatic life with proportions up to 70% mutation, progressive encephalopathy above 80% and severe Leigh-like syndrome above 95% mutation. One patient did not fit within that frame but presented with characteristics suggesting the presence of an additional disease.
    Mitochondrion 01/2014; · 4.03 Impact Factor
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    ABSTRACT: To report that homoplasmic deleterious mutations in the mitochondrial DNA MT-ATP6/8 genes may be responsible for acute episodes of limb weakness mimicking periodic paralysis due to channelopathies and dramatically responding to acetazolamide. Mitochondrial DNA sequencing and restriction PCR, oxidative phosphorylation functional assays, reactive oxygen species metabolism, and patch-clamp technique in cultured skin fibroblasts. Occurrence of a typical MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome in a single member of a large pedigree with episodic weakness associated with a later-onset distal motor neuropathy led to the disclosure of 2 deleterious mitochondrial DNA mutations. The MT-ATP6 m.9185T>C p.Leu220Pro mutation, previously associated with Leigh syndrome, was present in all family members, while the MT-TL1 m.3271T>C mutation, a known cause of MELAS syndrome, was observed in the sole patient with MELAS presentation. Significant defect of complexes V and I as well as oxidative stress were observed in both primary fibroblasts and cybrid cells with 100% m.9185T>C mutation. Permanent plasma membrane depolarization and altered permeability to K(+) in fibroblasts provided a link with the paralysis episodes. Screening of 9 patients, based on their clinical phenotype, identified 4 patients with similar deleterious MT-ATP6 mutations (twice m.9185T>C and once m.9176T>C or m.8893T>C). A fifth patient presented with an original potentially deleterious MT-ATP8 mutation (m.8403T>C). All mutations were associated with almost-normal complex V activity but significant oxidative stress and permanent plasma membrane depolarization. Homoplasmic mutations in the MT-ATP6/8 genes may cause episodic weakness responding to acetazolamide treatment.
    Neurology 10/2013; · 8.25 Impact Factor
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    ABSTRACT: Human mitochondrial diseases, defined as the diseases due to a mitochondrial oxidative phosphorylation defect, represent a large group of very diverse diseases with respect to phenotype and genetic causes. They present with many unsolved issues, the comprehensive analysis of which is beyond the scope of this review. We here essentially focus on the mechanisms underlying the diversity of targeted tissues, which is an important component of the large panel of these diseases phenotypic expression. The reproducibility of genotype/phenotype expression, the presence of modifying factors, and the potential causes for the restricted pattern of tissular expression are reviewed. Special emphasis is made on heteroplasmy, a specific feature of mitochondrial diseases, defined as the coexistence within the cell of mutant and wild type mitochondrial DNA molecules. Its existence permits unequal segregation during mitoses of the mitochondrial DNA populations and consequently heterogeneous tissue distribution of the mutation load. The observed tissue distributions of recurrent human mitochondrial DNA deleterious mutations are diverse but reproducible for a given mutation demonstrating that the segregation is not a random process. Its extent and mechanisms remain essentially unknown despite recent advances obtained in animal models.
    Biochimie 08/2013; · 3.14 Impact Factor
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    ABSTRACT: Mitochondrial mutations, an important cause of incurable human neuromuscular diseases, are mostly heteroplasmic: mutated mitochondrial DNA is present in cells simultaneously with wild-type genomes, the pathogenic threshold being generally >70% of mutant mtDNA. We studied whether heteroplasmy level could be decreased by specifically designed oligoribonucleotides, targeted into mitochondria by the pathway delivering RNA molecules in vivo. Using mitochondrially imported RNAs as vectors, we demonstrated that oligoribonucleotides complementary to mutant mtDNA region can specifically reduce the proportion of mtDNA bearing a large deletion associated with the Kearns Sayre Syndrome in cultured transmitochondrial cybrid cells. These findings may be relevant to developing of a new tool for therapy of mtDNA associated diseases.
    Nucleic Acids Research 10/2012; · 8.81 Impact Factor
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    ABSTRACT: We investigated a family in which the index subject presented with severe congenital lactic acidosis and dysmorphic features associated with a cytochrome c oxidase (COX)-assembly defect and a specific decrease in the synthesis of COX I, the subunit that nucleates COX assembly. Using a combination of microcell-mediated chromosome transfer, homozygosity mapping, and transcript profiling, we mapped the gene defect to chromosome 12 and identified a homozygous missense mutation (c.88G>A) in C12orf62. C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype. Furthermore, siRNA-mediated knockdown of C12orf 62 recapitulated the biochemical defect in control cells and exacerbated it in subject cells. C12orf62 is apparently restricted to the vertebrate lineage. It codes for a very small (6 kDa), uncharacterized, single-transmembrane protein that localizes to mitochondria and elutes in a complex of ∼110 kDa by gel filtration. COX I, II, and IV coimmunoprecipated with an epitope-tagged version of C12orf62, and 2D blue-native-polyacrylamide-gel-electrophoresis analysis of newly synthesized mitochondrial COX subunits in subject fibroblasts showed that COX assembly was impaired and that the nascent enzyme complex was unstable. We conclude that C12orf62 is required for coordination of the early steps of COX assembly with the synthesis of COX I.
    The American Journal of Human Genetics 01/2012; 90(1):142-51. · 11.20 Impact Factor
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    ABSTRACT: Coenzyme Q(10) (CoQ(10)) deficiency has been associated with an increasing number of clinical phenotypes. Whereas primary CoQ(10) defects are related to mutations in ubiquinone biosynthetic genes, which are now being unraveled, and respond well to CoQ(10) supplementation, the etiologies, and clinical phenotypes related to secondary deficiencies are largely unknown. The purpose of this multicenter study was to evaluate the frequency of muscle CoQ(10) deficiency in a cohort of 76 patients presenting with clinically heterogeneous mitochondrial phenotypes which included myopathy among their clinical features. A reliable diagnostic tool based on HPLC quantification was employed to measure muscle CoQ(10) levels. A significant proportion of these patients (28 over 76) displayed CoQ(10) deficiency that was clearly secondary in nine patients, who harbored a pathogenic mutation of mitochondrial DNA. This study provides a rationale for future therapeutic trials on the effect of CoQ(10) supplementation in patients with mitochondrial diseases presenting with myopathy among clinical features.
    Neuromuscular Disorders 11/2009; 20(1):44-8. · 3.46 Impact Factor
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    ABSTRACT: Members of the peroxisome proliferator-activated receptor gamma coactivator (PGC) family are potent inducers of mitochondrial biogenesis. We have tested the potential effect of increased mitochondrial biogenesis in cells derived from patients harboring oxidative phosphorylation defects due to either nuclear or mitochondrial DNA mutations. We found that the PGC-1alpha and/or PGC-1beta expression improved mitochondrial respiration in cells harboring a complex III or IV deficiency as well as in transmitochondrial cybrids harboring mitochondrial encephalomyopathy lactic acidosis and stroke A3243G tRNA((Leu)UUR) gene mutation. The respiratory function improvement was found to be associated with increased levels of mitochondrial components per cell, although this increase was not homogeneous. These results reinforce the concept that increased mitochondrial biogenesis is a promising venue for the treatment of mitochondrial diseases.
    Human Molecular Genetics 04/2009; 18(10):1805-12. · 7.69 Impact Factor
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    ABSTRACT: The prognosis of chronic progressive ophthalmoplegia with large-scale mitochondrial DNA (mtDNA) may strikingly vary from mild slowly progressive myopathy to severe multi-organ involvement. Evaluation of the disease course at the beginning of the disease is reputed impossible. To address the existence of predictive prognostic clues of these diseases, we classified 69 patients with chronic progressive ophthalmoplegia and large size mtDNA deletion into two groups according to the presence of manifestations from brain, inner ear or retina. These manifestations were present in 29 patients (CPEO/+N group) and absent in 40 patients (CPEO/-N group). We retrospectively established the clinical history of the patients and characterized their genetic alteration (amount of residual normal mtDNA molecules, site, size and percentage of the mtDNA deletion in 116 DNA samples from muscle, blood, urinary and buccal cells). In both clinical groups, the disease was progressive and heart conduction defects were frequent. We show that the CPEO/+N phenotype segregated with severe prognosis in term of rate of progression, multi-organs involvement and rate of survival. Age at onset appeared a predictive factor. The risk to develop a CPEO/+N phenotype was high when onset was before 9 years of age and low when onset was after 20 years of age. The presence and proportion of the mtDNA deletion in blood was also significantly associated with the CPEO/+N phenotype. This study is the first to establish the natural history of chronic ophthalmoplegia with mtDNA deletion in a large series of patients and to look for parameters potentially predictive of the patients' clinical course.
    Brain 07/2007; 130(Pt 6):1516-24. · 10.23 Impact Factor
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    ABSTRACT: Skin fibroblasts are essential tools for biochemical, genetic and physiopathological investigations of mitochondrial diseases. Their immortalization has been previously performed to overcome the limited number of divisions of these primary cells but it has never been systematically evaluated with respect to efficacy and impact on the oxidative phosphorylation (OXPHOS) characteristics of the cells. We successfully immortalized with the human telomerase gene 15 human fibroblasts populations, 4 derived from controls and 11 from patients with diverse respiratory chain defects. Immortalization induced significant but mild modification of the OXPHOS characteristics of the cells with lower rates of oxygen consumption and ATP synthesis associated with their loose coupling. However, it never significantly altered the type and severity of any genetic OXPHOS defect present prior to immortalization. Furthermore, it did not significantly modify the cells' dependence on glucose and sensitivity to galactose thus showing that immortalized cells could be screened by their nutritional requirement. Immortalized skin fibroblasts with significant OXPHOS defect provide reliable tools for the diagnosis and research of the genetic cause of mitochondrial defects. They also represent precious material to investigate the cellular responses to these defects, even though these should afterwards be verified in unmodified primary cells.
    Neuromuscular Disorders 06/2007; 17(5):368-75. · 3.46 Impact Factor
  • K Auré, A Lombès
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    ABSTRACT: Mitochondrial respiratory chain abnormalities are a cause of neuromuscular diseases. They present with very diverse clinical presentations,involving either the central nervous system, the peripheral nervous system, or skeletal muscle, and may be due to mutations either in mitochondrial or nuclear genome. The aim of this review is to familiarise the clinician with these diseases, to evoke main syndromes, and to give guidelines for their diagnostic investigation.
    Revue Neurologique 03/2007; 163(2):254-63. · 0.51 Impact Factor
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    ABSTRACT: Mitochondria form a dynamic network in which continuous movement, fusion, and division ensure the distribution and exchange of proteins and deoxyribonucleic acid (DNA). The recent past has seen the identification and characterization of the first proteins governing the organization, function, and dynamics of mitochondria and mitochondrial DNA, and it is predictable that numerous new proteins will require localization and functional characterization in the future. In this chapter, we describe methods for the visualization of mitochondria and mitochondrial activity in cultured mammalian cells to establish the localization or distribution of its components and to study mitochondrial fusion.
    Methods in molecular biology (Clifton, N.J.) 02/2007; 372:3-16. · 1.29 Impact Factor
  • K. Auré, A. Lombès
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    ABSTRACT: Mitochondrial respiratory chain abnormalities are a cause of neuromuscular diseases. They present with very diverse clinical presentations,involving either the central nervous system, the peripheral nervous system, or skeletal muscle, and may be due to mutations either in mitochondrial or nuclear genome. The aim of this review is to familiarise the clinician with these diseases, to evoke main syndromes, and to give guidelines for their diagnostic investigation.
    Revue Neurologique - REV NEUROL. 01/2007; 163(2):254-263.
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    ABSTRACT: Although a rare entity, multiple gliomas must be recognized and distinguished from other causes of multiple brain lesions. Clinical and radiological features of 33 multiple gliomas were reviewed, including 20 synchronous cases and 13 metachronous cases. In 17 patients, radiological features were highly suggestive of spread from a primary site (multifocal gliomas). No apparent dissemination route was identified in the other cases which were presumed to be multicentric gliomas. For nine patients (27 percent), a second neoplasia or cancer was found in first degree relatives suggesting a genetic predisposition. Overall median survival was 79 weeks (64 weeks for glioblastomas). The age at onset was the main prognostic factor. Multiple gliomas represent a heterogeneous entity, probably corresponding to different mechanisms. In our group, survival was comparable to unique glioma.
    Revue Neurologique 10/2006; 162(8-9):845-51. · 0.51 Impact Factor
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    ABSTRACT: Increased susceptibility to apoptosis has been shown in many models of mitochondrial defects but its relevance to human diseases is still discussed. We addressed the presence of apoptosis in muscle from patients with mitochondrial DNA (mtDNA) disorders. Taking advantage of the mosaic pattern of muscle morphological anomalies associated with heteroplasmic mtDNA alterations, we have used an in situ approach to address the relationship between apoptosis and respiratory defect, mitochondrial proliferation and mutation load. Different patterns of mitochondrial morphological alterations were provided by the analysis of muscles with large mtDNA deletion (16 cases) or with the MELAS mutation (4 cases). The patient's age at biopsy ranged from 0.4 to 66 years and the muscle mutant mtDNA proportion from 32 to 82%. Apoptotic muscle fibres were observed in a small proportion of muscle fibres of 16 out of the 20 biopsies by three different detection methods for different steps of apoptosis: caspase 3 activation, fragmentation of nuclear DNA [terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay] or overexpression of the pro-apoptotic factor Bax. Analysis of apoptotic features in parallel to cytochrome c oxidase (COX) and succinate dehydrogenase activity of more than 34,000 individual muscle fibres showed that apoptosis occurred only in muscle fibres with mitochondrial proliferation (ragged red fibres, RRF) irrespective of their COX activity. Molecular analyses of single muscle fibres evidenced that, as expected, the presence of COX defect was associated with higher proportion of mutant mtDNA and lower amount of normal mtDNA. Within COX-defective fibres, the presence of mitochondrial proliferation was associated with increase of the mtDNA content but without change in the ratio between normal and mutant mtDNA molecules, thus showing that mitochondrial proliferation was accompanied by similar amplification of normal and mutant mtDNA molecules. Within RRF, apoptosis was associated with higher mutation proportion, suggesting that it was provoked by severe respiratory defect in the same time as increased mitochondrial mass. In conclusion, apoptosis most probably contributes to mitochondrial pathology. It is tightly linked to mitochondrial proliferation and high mutation load. When considering training therapeutics, one will have to take into account the possibility to induce apoptosis in parallel to mitochondrial proliferation.
    Brain 06/2006; 129(Pt 5):1249-59. · 10.23 Impact Factor
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    ABSTRACT: Introduction Although a rare entity, multiple gliomas must be recognized and distinguished from other causes of multiple brain lesions. Methods Clinical and radiological features of 33 multiple gliomas were reviewed, including 20 synchronous cases and 13 metachronous cases. Results In 17 patients, radiological features were highly suggestive of spread from a primary site (multifocal gliomas). No apparent dissemination route was identified in the other cases which were presumed to be multicentric gliomas. For nine patients (27 percent), a second neoplasia or cancer was found in first degree relatives suggesting a genetic predisposition. Overall median survival was 79 weeks (64 weeks for glioblastomas). The age at onset was the main prognostic factor. Conclusion Multiple gliomas represent a heterogeneous entity, probably corresponding to different mechanisms. In our group, survival was comparable to unique glioma.
    Revue Neurologique - REV NEUROL. 01/2006; 162(8):845-851.
  • Karine Auré, Claude Jardel, Anne Lombès
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    ABSTRACT: Mitochondrial diseases are relatively common inherited metabolic diseases due to mitochondrial respiratory chain dysfunction. Their clinical presentation is extremely diverse, multisystemic or confined to a single tissue, sporadic or transmitted, by maternal or mendelian inheritance. The diagnosis of mitochondrial disorders is difficult. It is based upon several types of clues both clinical (family history, type of symptoms but also their association in syndromic presentation,...) and biological (alteration of the lactate metabolism, brain imaging, morphological alterations especially of muscle tissue). The diagnosis relies upon the demonstration of a defect of the respiratory chain activities and/or upon the identification of the underlying genetic alteration. Molecular diagnosis remains quite difficult and up to-date concerns essentially mitochondrial DNA mutations. On one hand, clinical and biological presentations as well as enzymatic defects lack specificity. On the other hand, candidate genes are very numerous and part of them are probably still unknown.
    Annales de Pathologie 10/2005; 25(4):270-81. · 0.24 Impact Factor
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    Journal of Neurology Neurosurgery & Psychiatry 10/2005; 76(9):1305-6. · 4.92 Impact Factor
  • Karine Auré, Claude Jardel, Anne Lombès
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial diseases are relatively common inherited metabolic diseases due to mitochondrial respiratory chain dysfunction. Their clinical presentation is extremely diverse, multisystemic or confined to a single tissue, sporadic or transmitted, by maternal or mendelian inheritance. The diagnosis of mitochondrial disorders is difficult. It is based upon several types of clues both clinical (family history, type of symptoms but also their association in syndromic presentation,…) and biological (alteration of the lactate metabolism, brain imaging, morphological alterations especially of muscle tissue). The diagnosis relies upon the demonstration of a defect of the respiratory chain activities and/or upon the identification of the underlying genetic alteration. Molecular diagnosis remains quite difficult and up to-date concerns essentially mitochondrial DNA mutations. On one hand, clinical and biological presentations as well as enzymatic defects lack specificity. On the other hand, candidate genes are very numerous and part of them are probably still unknown.
    Annales De Pathologie - ANN PATHOL. 01/2005; 25(4):270-281.
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    ABSTRACT: The authors report 7 years of follow-up evaluation of a patient with coenzyme Q10 (CoQ10) deficiency. Initial symptoms of exercise intolerance and hyperlactatemia improved markedly with substitutive treatment. However, CoQ(10) supplementation did not prevent the onset of a cerebellar syndrome. A switch to idebenone treatment resulted in clinical and metabolic worsening, which disappeared with subsequent CoQ10 treatment. CoQ10 defects may cause progressive neurologic disease despite supplementation.
    Neurology 09/2004; 63(4):727-9. · 8.25 Impact Factor
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    ABSTRACT: We report the clinical features of two unrelated patients, a 51-year-old woman and a 54-year-old man, presenting proximal myopathy with lipomatosis. In both patients, muscle biopsies showed numerous ragged-red fibers. Molecular analysis were performed with denaturating gradient gel electrophoresis (DGGE) on muscle, blood, hair, buccal and urinary cells. The A8344G mutation of the tRNA-lysine gene of the mitochondrial DNA was detected in all tissues at high levels (more than 80 p cent). None of the patients had a contributive family history, and signs of central nervous system involvement were absent. These observations confirm that lipomatosis may be encountered in mitochondrial disorders and is tightly associated with the A8344G mutation.
    Revue Neurologique 01/2004; 159(12):1163-8. · 0.51 Impact Factor

Publication Stats

231 Citations
86.73 Total Impact Points

Institutions

  • 2004–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2012
    • Hôpital Ambroise Paré – Hôpitaux universitaires Paris Ile-de-France Ouest
      Billancourt, Île-de-France, France
  • 2006–2007
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2004–2006
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      • Service de Neurochirurgie
      Lutetia Parisorum, Île-de-France, France