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378 results on '"Schuelke, M."'

1. Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Author

Wilpert NM, Tonduti D, Vaia Y, Krude H, Sarret C, and Schuelke M

Subjects
mct8 deficiency, slc16a2, ultra-rare disease, movement disorders, triac, stakeholder engagement, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Nina-Maria Wilpert,1,2 Davide Tonduti,3 Ylenia Vaia,3 Heiko Krude,4 Catherine Sarret,5 Markus Schuelke1,2,6 1Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Pediatric Neurology, Berlin, Germany; 2Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Center for Chronically Sick Children, Berlin, Germany; 3Unit of Pediatric Neurology, C.O.A.L.A. (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, Università Degli Studi Di Milano, Milan, Italy; 4Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Experimental Pediatric Endocrinology, Berlin, Germany; 5Centre de Compétence des Leucodystrophies et Leucoencéphalopathies de Cause Rare, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France; 6Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), NeuroCure Clinical Research Center, Berlin, GermanyCorrespondence: Markus Schuelke, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany, Tel +49 30 450566468, Email markus.schuelke@charite.deIntroduction: The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients’ perspective and identify clinical endpoints that are clinically relevant to their daily life.Methods: We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.Results: We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5– 9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.Discussion: We recommend that future trials should define a relevant improvement in “development” and/or other patient-relevant outcomes compared to natural history as treatment goals.Keywords: MCT8 deficiency, SLC16A2, ultra-rare disease, movement disorders, Triac, stakeholder engagement

Published
2023

2. Upgrades of edge, divertor and scrape-off layer diagnostics of W7‐X for OP1.2

Author

Hathiramani, D., Ali, A., Anda, G., Barbui, T., Biedermann, C., Charl, A., Chauvin, D., Czymek, G., Dhard, C.P., Drewelow, P., Dudek, A., Effenberg, F., Ehrke, G., Endler, M., Ennis, D.A., Fellinger, J., Ford, O., Freundt, S., Gradic, D., Grosser, K., Harris, J., Hölbe, H., Jakubowski, M.W., Knaup, M., Kocsis, G., König, R., Krause, M., Kremeyer, T., Kornejew, P., Krychowiak, M., Lambertz, H.T., Jenzsch, H., Mayer, M., Mohr, S., Neubauer, O., Otte, M., Perseo, V., Pilopp, D., Rudischhauser, L., Schmitz, O., Schweer, B., Schülke, M., Stephey, L., Szepesi, T., Terra, A., Toth, M., Wenzel, U., Wurden, G.A., Zoletnik, S., and Pedersen, T. Sunn

Published
2018
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4. Generation of two mother-child pairs of iPSCs from maternally inherited Leigh syndrome patients with m.8993 T > G and m.9176 T > G MT-ATP6 mutations

Author

Henke, M.T., Zink, A., Diecke, S., Prigione, A., and Schuelke, M.

Subjects
Technology Platforms
Abstract

We generated two pairs of mother-child iPSCs lines for Maternally Inherited Leigh Syndrome (MILS) carrying the m.8993 T > G and m.9176 T > G mutations in the MT-ATP6 gene. We delivered reprogramming factors OCT4, SOX2, KLF4, and c-MYC via Sendai virus. All iPSCs lines had a normal karyotype, expressed pluripotency markers, and differentiated into the three germ layers. Both patient-iPSCs retained the same degrees of heteroplasmy as their source fibroblasts (>97.0 %). In maternal iPSCs, the heteroplasmy remained 0.0 % in the case of the m.8993 T > G mutation and dropped from 55.0 % to 1.0 % in the case of m.9176 T > G mutation.

Published
2023

9. Generation of four iPSC lines from four patients with Leigh syndrome carrying homoplasmic mutations m.8993T > G or m.8993T > C in the mitochondrial gene MT-ATP6

Author

Lorenz, C., Zink, A., Henke, M.T., Staege, S., Mlody, B., Bünning, M., Wanker, E., Diecke, S., Schuelke, M., and Prigione, A.

Subjects
Function and Dysfunction of the Nervous System
Abstract

We report the generation of four human iPSC lines (8993-A12, 8993-B12, 8993-C11, and 8993-D7) from fibroblasts of four patients affected by maternally inherited Leigh syndrome (MILS) carrying homoplasmic mutations m.8993T > G or m.8993T > C in the mitochondrial gene MT-ATP6. We used Sendai viruses to deliver reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The established iPSC lines expressed pluripotency markers, exhibited a normal karyotype, were capable to form cells of the three germ layers in vitro, and retained the MT-ATP6 mutations at the same homoplasmic level of the parental fibroblasts.

Published
2022

12. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination

Author

Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., Zorzi, R. de, Payne, K., Henderson, L.B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J.A., Provitera, V., Schuelke, M., Vandrovcova, J., Groppa, S., Karashova, B.M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J.S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M.D., Maagdenberg, A.M.J.M. van den, Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A.M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B.M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E.Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N.N., Atawneh, O., Lim, S.Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y.A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E.G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., Lonlay, P. de, Cantagrel, V., Aguennouz, M., Khorassani, M. el, Schmidts, M., Alkuraya, F.S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., SYNAPS Study Grp, Efthymiou, S., Salpietro, V., Malintan, N., Poncelet, M., Kriouile, Y., Fortuna, S., De Zorzi, R., Payne, K., Henderson, L. B., Cortese, A., Maddirevula, S., Alhashmi, N., Wiethoff, S., Ryten, M., Botia, J. A., Provitera, V., Schuelke, M., Vandrovcova, J., Walsh, L., Torti, E., Iodice, V., Najafi, M., Karimiani, E. G., Maroofian, R., Siquier-Pernet, K., Boddaert, N., De Lonlay, P., Cantagrel, V., Aguennouz, M., El Khorassani, M., Schmidts, M., Alkuraya, F. S., Edvardson, S., Nolano, M., Devaux, J., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Goraya, J. S., Sultan, T., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Van Den Maagdenberg, A. M. J. M., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Rothman, J., Kullmann, D., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Lim, S. -Y., Shaikh, F., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Minetti, C., Al-Khawaja, I., Al-Mutairi, F., Hamed, S., Pipis, M., Bettencourt, C., Rinaldi, S., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratory of Molecular Biophysics, Department of Biochemistry, Department of Biochemistry, Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen, Department of Medical and Molecular Genetics, King‘s College London, Department of Human Genetics, Ruhr University Bochum (RUB), Universitat de Barcelona (UB), Fondazione, Leiden University Medical Center (LUMC), Department of Physiology and Cellular Biophysics [New York, NY, USA], Columbia University College of Physicians and Surgeons, Department of Microbiology, Università degli studi di Catania [Catania], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ceinge, centro di Ingegneria Genetica e Biotecnologie Avanzate, Unité des troubles du sommeil, Centre de référence national sur les maladies rares (narcolepsie, hypersomnie idiopathique, syndrome de Kleine-Levin)-Hôpital Gui-de-Chauliac, Muscular and Neurodegenerative Disease Unit, University of Genoa (UNIGE), Department of Molecular Neuroscience, University College of London [London] (UCL)-Institute of Neurology, Indiana University, Indiana University [Bloomington], Indiana University System-Indiana University System, Molecular and Clinical Sciences Institute - St George’s [London, UK] (Genetics Research Centre), University of London [London], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie en psychiatrie (U1000), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service métabolisme, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Efthymiou S., Salpietro V., Malintan N., Poncelet M., Kriouile Y., Fortuna S., De Zorzi R., Payne K., Henderson L.B., Cortese A., Maddirevula S., Alhashmi N., Wiethoff S., Ryten M., Botia J.A., Provitera V., Schuelke M., Vandrovcova J., Walsh L., Torti E., Iodice V., Najafi M., Karimiani E.G., Maroofian R., Siquier-Pernet K., Boddaert N., De Lonlay P., Cantagrel V., Aguennouz M., El Khorassani M., Schmidts M., Alkuraya F.S., Edvardson S., Nolano M., Devaux J., Houlden H., Groppa S., Karashova B.M., Nachbauer W., Boesch S., Arning L., Timmann D., Cormand B., Perez-Duenas B., Goraya J.S., Sultan T., Mine J., Avdjieva D., Kathom H., Tincheva R., Banu S., Pineda-Marfa M., Veggiotti P., Ferrari M.D., Van Den Maagdenberg A.M.J.M., Verrotti A., Marseglia G., Savasta S., Garcia-Silva M., Ruiz A.M., Garavaglia B., Borgione E., Portaro S., Sanchez B.M., Boles R., Papacostas S., Vikelis M., Rothman J., Kullmann D., Papanicolaou E.Z., Dardiotis E., Maqbool S., Ibrahim S., Kirmani S., Rana N.N., Atawneh O., Lim S.-Y., Shaikh F., Koutsis G., Breza M., Mangano S., Scuderi C., Morello G., Stojkovic T., Zollo M., Heimer G., Dauvilliers Y.A., Minetti C., Al-Khawaja I., Al-Mutairi F., Hamed S., Pipis M., Bettencourt C., Rinaldi S., Efthymiou, Stephanie, Salpietro, Vincenzo, Malintan, Nancy, Poncelet, Mallory, Kriouile, Yamna, Fortuna, Sara, De Zorzi, Rita, Payne, Katelyn, Henderson, Lindsay B, Cortese, Andrea, Maddirevula, Sateesh, Alhashmi, Nadia, Wiethoff, Sarah, Ryten, Mina, Botia, Juan A, Provitera, Vincenzo, Schuelke, Marku, Vandrovcova, Jana, Walsh, Laurence, Torti, Erin, Iodice, Valeria, Najafi, Maryam, Karimiani, Ehsan Ghayoor, Maroofian, Reza, Siquier-Pernet, Karine, Boddaert, Nathalie, De Lonlay, Pascale, Cantagrel, Vincent, Aguennouz, Mhammed, El Khorassani, Mohamed, Schmidts, Miriam, Alkuraya, Fowzan S, Edvardson, Simon, Nolano, Maria, Devaux, Jérôme, Houlden, Henry, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Male, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Nerve Fibers, Myelinated, Gene Frequency, Neurodevelopmental Disorder, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Nerve Growth Factor, Protein Isoforms, Child, ComputingMilieux_MISCELLANEOUS, Myelin Sheath, neurofascin, neurodevelopment, peripheral demyelination, Allele, Demyelinating Disease, Genomics, neurodevelopment, neurofascin, peripheral demyelination, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, Peripheral Nerve, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neuroglia, Human, Adult, Adolescent, Nervous System Malformations, Guillain-Barre Syndrome, Axon, Nervous System Malformation, Ranvier's Nodes, Humans, Nerve Growth Factors, Peripheral Nerves, Alleles, Autoantibodies, Infant, Protein Isoform, Original Articles, Axons, nervous system, Neurodevelopmental Disorders, Cell Adhesion Molecule, Mutation, Cell Adhesion Molecules, Demyelinating Diseases
Abstract

See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres., Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

Published
2019

13. DMD – ANIMAL MODELS

Author

Morin, A., primary, Petrova, O., additional, Petkova, M., additional, Tensorer, T., additional, Manoliu, T., additional, Richard, I., additional, Garcia, L., additional, Schuelke, M., additional, Laplace-Builhé, C., additional, Goyenvalle, A., additional, Stantzou, A., additional, and Amthor, H., additional

Published
2021
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16. Das Deutsche Netzwerk für mitochondriale Erkrankungen (mitoNET)

Author

Büchner, B., Gallenmüller, C., Lautenschläger, R., Kuhn, K., Wittig, I., Schöls, L., Rapaport, D., Seelow, D., Freisinger, P., Prokisch, H., Sperl, W., Wenz, T., Behl, C., Deschauer, M., Kornblum, C., Schneiderat, P., Abicht, A., Schuelke, M., Meitinger, T., Klopstock, T., and und das mitoNET-Consortium

Published
2012
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19. Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis

Author

Gusic, Mirjana, Schottmann, G., Feichtinger, R.G., Du, Chen, Scholz, Caroline, Wagner, Matias, Panneman, D.M., Rodenburg, R.J., Prokisch, H., Schuelke, M., Gusic, Mirjana, Schottmann, G., Feichtinger, R.G., Du, Chen, Scholz, Caroline, Wagner, Matias, Panneman, D.M., Rodenburg, R.J., Prokisch, H., and Schuelke, M.

Abstract

Contains fulltext : 215007.pdf (publisher's version ) (Closed access)

Published
2020

21. Live‐imaging of revertant and therapeutically restored dystrophin in the DmdEGFP‐mdx mouse model for Duchenne muscular dystrophy

Author

Petkova, M. V., primary, Stantzou, A., additional, Morin, A., additional, Petrova, O., additional, Morales‐Gonzalez, S., additional, Seifert, F., additional, Bellec‐Dyevre, J., additional, Manoliu, T., additional, Goyenvalle, A., additional, Garcia, L., additional, Richard, I., additional, Laplace‐Builhé, C., additional, Schuelke, M., additional, and Amthor, H., additional

Published
2020
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27. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), Wortmann, S.B. (S.), Repp, B.M. (Birgit M.), Mastantuono, E. (Elisa), Alston, C.L. (Charlotte L.), Schiff, M. (Manuel), Haack, T.B. (Tobias B.), Rötig, A. (Agns), Ardissone, A. (Anna), Lombès, A. (Anne), Catarino, C.F.B.S., Diodato, D. (Daria), Schottmann, G. (Gudrun), Poulton, J. (Joanna), Burlina, A.B. (Alberto), Jonckheere, A. (An), Munnich, A. (Arnold), Rolinski, B. (Boris), Ghezzi, D. (Daniele), Rokicki, D. (Dariusz), Wellesley, D. (Diana), Martinelli, D. (Diego), Wenhong, D. (Ding), Lamantea, E. (Eleonora), Østergaard, E. (Elsebet), Pronicka, E. (Ewa), Pierre, G. (Germaine), Smeets, H.J.M. (Hubert), Wittig, I. (Ilka), Scurr, I. (Ingrid), Coo, I.F.M. (René) de, Moroni, I. (Isabella), Smet, J. (Joél), Mayr, J.A. (Johannes A.), Dai, L. (Lifang), Meirleir, L. (Linda) de, Schuelke, M. (Markus), Zeviani, M. (Massimo), Morscher, R.J. (Raphael J.), McFarland, R. (Robert), Seneca, S. (S.), Klopstock, T. (Thomas), Meitinger, T. (Thomas), Wieland, T. (Thomas), Strom, T.M. (Tim), Herberg, U. (Ulrike), Ahting, U. (Uwe), Sperl, W. (Wolfgang), Nassogne, M.C. (M.), Ling, H. (Han), Fang, F. (Fang), Freisinger, P. (Peter), Coster, R.N.A. (R. N A) van, Strecker, V. (Valentina), Taylor, R.W. (Robert William), Häberle, J. (Johannes), Vockley, J. (Jerry), Prokisch, H. (Holger), and Wortmann, S.B. (S.)

Abstract

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 s

Published
2018
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28. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Author

Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, Wortmann, Saskia, Repp, B, Mastantuono, E, Alston, C, Schiff, M, Haack, T, Rötig, A, Ardissone, A, Lombès, A, Catarino, C, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Wenhong, D, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, H, Wittig, I, Scurr, I, De Coo, I, Moroni, I, Smet, J, Mayr, J, Dai, L, De Meirleir, L, Schuelke, M, Zeviani, M, Morscher, R, Mcfarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, T, Herberg, U, Ahting, U, Sperl, W, Nassogne, M, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, R, Häberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, Birgit M., Mastantuono, Elisa, Alston, Charlotte L., Schiff, Manuel, Haack, Tobias B., Rötig, Agnes, Ardissone, Anna, Lombès, Anne, Catarino, Claudia B., Diodato, Daria, Schottmann, Gudrun, Poulton, Joanna, Burlina, Alberto, Jonckheere, An, Munnich, Arnold, Rolinski, Boris, Ghezzi, Daniele, Rokicki, Dariusz, Wellesley, Diana, Martinelli, Diego, Wenhong, Ding, Lamantea, Eleonora, Ostergaard, Elsebet, Pronicka, Ewa, Pierre, Germaine, Smeets, Hubert J. M., Wittig, Ilka, Scurr, Ingrid, De Coo, Irenaeus F. M., Moroni, Isabella, Smet, Joél, Mayr, Johannes A., Dai, Lifang, De Meirleir, Linda, Schuelke, Markus, Zeviani, Massimo, Morscher, Raphael J., McFarland, Robert, Seneca, Sara, Klopstock, Thomas, Meitinger, Thomas, Wieland, Thomas, Strom, Tim M., Herberg, Ulrike, Ahting, Uwe, Sperl, Wolfgang, Nassogne, Marie-Cecile, Ling, Han, Fang, Fang, Freisinger, Peter, Van Coster, Rudy, Strecker, Valentina, Taylor, Robert W., Häberle, Johannes, Vockley, Jerry, Prokisch, Holger, and Wortmann, Saskia

Abstract

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.

Published
2018

29. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Author

Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, Wortmann, S, Repp, BM, Mastantuono, E, Alston, CL, Schiff, M, Haack, TB, Rotig, A, Ardissone, A, Lombes, A, Catarino, CB, Diodato, D, Schottmann, G, Poulton, J, Burlina, A, Jonckheere, A, Munnich, A, Rolinski, B, Ghezzi, D, Rokicki, D, Wellesley, D, Martinelli, D, Ding, WH, Lamantea, E, Ostergaard, E, Pronicka, E, Pierre, G, Smeets, HJM, Wittig, I, Scurr, I, Coo, IFM, Moroni, I, Smet, J, Mayr, JA, Dai, LF, de Meirleir, L, Schuelke, M, Zeviani, M, Morscher, RJ, McFarland, R, Seneca, S, Klopstock, T, Meitinger, T, Wieland, T, Strom, TM, Herberg, U, Ahting, U, Sperl, W, Nassogne, MC, Ling, H, Fang, F, Freisinger, P, Van Coster, R, Strecker, V, Taylor, RW, Haberle, J, Vockley, J, Prokisch, H, and Wortmann, S

Published
2018

31. Extracellular matrix remodelling is associated with muscle force increase in overloaded mouse plantaris muscle.

Author

Stantzou, A., Relizani, K., Morales‐Gonzalez, S., Gallen, C., Grassin, A., Ferry, A., Schuelke, M., and Amthor, H.

Subjects
EXTRACELLULAR matrix, MUSCLES, MUSCULAR dystrophy, MUSCLE growth, MUSCLE mass
Abstract

Aims: Transforming growth factor‐β (TGF‐β) signalling is thought to contribute to the remodelling of extracellular matrix (ECM) of skeletal muscle and to functional decline in patients with muscular dystrophies. We wanted to determine the role of TGF‐β‐induced ECM remodelling in dystrophic muscle. Methods: We experimentally induced the pathological hallmarks of severe muscular dystrophy by mechanically overloading the plantaris muscle in mice. Furthermore, we determined the role of TGF‐β signalling on dystrophic tissue modulation and on muscle function by (i) overloading myostatin knockout (Mstn−/−) mice and (ii) by additional pharmacological TGF‐β inhibition via halofuginone. Results: Transcriptome analysis of overloaded muscles revealed upregulation predominantly of genes associated with ECM, inflammation and metalloproteinase activity. Histology revealed in wild‐type mice signs of severe muscular dystrophy including myofibres with large variation in size and internalized myonuclei, as well as increased ECM deposition. At the same time, muscle weight had increased by 208% and muscle force by 234%. Myostatin deficiency blunted the effect of overload on muscle mass (59% increase) and force (76% increase), while having no effect on ECM deposition. Concomitant treatment with halofuginone blunted overload‐induced muscle hypertrophy and muscle force increase, while reducing ECM deposition and increasing myofibre size. Conclusions: ECM remodelling is associated with an increase in muscle mass and force in overload‐modelled dystrophic muscle. Lack of myostatin is not advantageous and inhibition of ECM deposition by halofuginone is disadvantageous for muscle plasticity in response to stimuli that induce dystrophic muscle. [ABSTRACT FROM AUTHOR]

Published
2021
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32. BMP signaling regulates satellite cell dependent postnatal muscle growth

Author

Stantzou, A., Schirwis, E., Swist, S., Alonso-Martin, S., Polydorou, I., Zarrouki, F., Mouisel, E., Beley, C., Julien, A., Le Grand, F., Garcia, L., Colnot, C., Birchmeier, C., Braun, T., Schuelke, M., Relaix, F., and Amthor, H.

Subjects
embryonic structures, Function and Dysfunction of the Nervous System
Abstract

Postnatal growth of skeletal muscle largely depends on the expansion and differentiation of resident stem cells, the so-called satellite cells. Here we demonstrate that postnatal satellite cells express components of the Bone Morphogenetic Protein (BMP) signaling machinery. Overexpression of Noggin in postnatal mice, to antagonize BMP ligands, or satellite cell specific knock-out of BMP transmembrane receptor Alk3, or overexpression of inhibitory SMAD6 decreased satellite cell proliferation and accretion during myofiber growth and ultimately retarded muscle growth. Moreover, reduced BMP signaling diminished the adult satellite cell pool. Abrogation of BMP signaling in satellite cell-derived primary myoblasts strongly diminished cell proliferation and up-regulated the expression of cell cycle inhibitors p21 and p57 In conclusion, these results show that BMP signaling defines postnatal muscle development by regulating satellite cell dependent myofiber growth and the generation of the adult muscle stem cell pool.

Published
2017

33. Live‐imaging of revertant and therapeutically restored dystrophin in the DmdEGFP‐mdx mouse model for Duchenne muscular dystrophy.

Author

Petkova, M. V., Stantzou, A., Morin, A., Petrova, O., Morales‐Gonzalez, S., Seifert, F., Bellec‐Dyevre, J., Manoliu, T., Goyenvalle, A., Garcia, L., Richard, I., Laplace‐Builhé, C., Schuelke, M., and Amthor, H.

Subjects
DUCHENNE muscular dystrophy, DYSTROPHIN, CHIMERIC proteins, NATURAL fibers, MICE, RETINA
Abstract

Background: Dmdmdx, harbouring the c.2983C>T nonsense mutation in Dmd exon 23, is a mouse model for Duchenne muscular dystrophy (DMD), frequently used to test therapies aimed at dystrophin restoration. Current translational research is methodologically hampered by the lack of a reporter mouse model, which would allow direct visualization of dystrophin expression as well as longitudinal in vivo studies. Methods: We generated a DmdEGFP‐mdx reporter allele carrying in cis the mdx‐23 mutation and a C‐terminal EGFP‐tag. This mouse model allows direct visualization of spontaneously and therapeutically restored dystrophin‐EGFP fusion protein either after natural fibre reversion, or for example, after splice modulation using tricyclo‐DNA to skip Dmd exon 23, or after gene editing using AAV‐encoded CRISPR/Cas9 for Dmd exon 23 excision. Results: Intravital microscopy in anaesthetized mice allowed live‐imaging of sarcolemmal dystrophin‐EGFP fusion protein of revertant fibres as well as following therapeutic restoration. Dystrophin‐EGFP‐fluorescence persisted ex vivo, allowing live‐imaging of revertant and therapeutically restored dystrophin in isolated fibres ex vivo. Expression of the shorter dystrophin‐EGFP isoforms Dp71 in the brain, Dp260 in the retina, and Dp116 in the peripheral nerve remained unabated by the mdx‐23 mutation. Conclusion: Intravital imaging of DmdEGFP‐mdx muscle permits novel experimental approaches such as the study of revertant and therapeutically restored dystrophin in vivo and ex vivo. [ABSTRACT FROM AUTHOR]

Published
2020
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35. METABOLIC MYOPATHIES I

Author

Pehl, D., primary, von Renesse, A., additional, Harms, L., additional, Goebel, H., additional, Schuelke, M., additional, and Stenzel, W., additional

Published
2018
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37. Coenzyme Q deficiency causes impairment of the sulfide oxidation pathway

Author

Ziosi, M., Meo, I. Di, Kleiner, G., Gao, X.H., Barca, E., Sanchez-Quintero, M.J., Tadesse, S., Jiang, H., Qiao, C., Rodenburg, R.J.T., Scalais, E., Schuelke, M., Willard, B., Hatzoglou, M., Tiranti, V., Quinzii, C.M., Ziosi, M., Meo, I. Di, Kleiner, G., Gao, X.H., Barca, E., Sanchez-Quintero, M.J., Tadesse, S., Jiang, H., Qiao, C., Rodenburg, R.J.T., Scalais, E., Schuelke, M., Willard, B., Hatzoglou, M., Tiranti, V., and Quinzii, C.M.

Abstract

Contains fulltext : 170060.pdf (publisher's version ) (Open Access), Coenzyme Q (CoQ) is an electron acceptor for sulfide-quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Here, we show that lack of CoQ in human skin fibroblasts causes impairment of hydrogen sulfide oxidation, proportional to the residual levels of CoQ. Biochemical and molecular abnormalities are rescued by CoQ supplementation in vitro and recapitulated by pharmacological inhibition of CoQ biosynthesis in skin fibroblasts and ADCK3 depletion in HeLa cells. Kidneys of Pdss2kd/kd mice, which only have ~15% residual CoQ concentrations and are clinically affected, showed (i) reduced protein levels of SQR and downstream enzymes, (ii) accumulation of hydrogen sulfides, and (iii) glutathione depletion. These abnormalities were not present in brain, which maintains ~30% residual CoQ and is clinically unaffected. In Pdss2kd/kd mice, we also observed low levels of plasma and urine thiosulfate and increased blood C4-C6 acylcarnitines. We propose that impairment of the sulfide oxidation pathway induced by decreased levels of CoQ causes accumulation of sulfides and consequent inhibition of short-chain acyl-CoA dehydrogenase and glutathione depletion, which contributes to increased oxidative stress and kidney failure.

Published
2017

40. Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement

Author

Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., Klopstock, T., Haack, T.B., Jackson, C.B., Murayama, K., Kremer, L.S., Schaller, A., Kotzaeridou, U., Vries, M.C. de, Schottmann, G., Santra, S., Büchner, B., Wieland, T., Graf, E., Freisinger, P., Eggimann, S., Ohtake, A., Okazaki, Y., Kohda, M., Kishita, Y., Tokuzawa, Y., Sauer, S., Memari, Y., Kolb-Kokocinski, A., Durbin, R., Hasselmann, O., Cremer, K., Albrecht, B., Wieczorek, D., Engels, H., Hahn, D., Zink, A.M., Alston, C.L., Taylor, R.W., Rodenburg, R.J., Trollmann, R., Sperl, W., Strom, T.M., Hoffmann, G.F., Mayr, J.A., Meitinger, T., Bolognini, R., Schuelke, M., Nuoffer, J.M., Kölker, S., Prokisch, H., and Klopstock, T.

Abstract

Contains fulltext : 154949.pdf (publisher's version ) (Open Access)

Published
2015

41. TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies

Author

Powell, C.A., Kopajtich, R., D'Souza, A.R., Rorbach, J., Kremer, L.S., Husain, R.A., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R.G., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H., Minczuk, M., Powell, C.A., Kopajtich, R., D'Souza, A.R., Rorbach, J., Kremer, L.S., Husain, R.A., Dallabona, C., Donnini, C., Alston, C.L., Griffin, H., Pyle, A., Chinnery, P.F., Strom, T.M., Meitinger, T., Rodenburg, R.J., Schottmann, G., Schuelke, M., Romain, N., Haller, R.G., Ferrero, I., Haack, T.B., Taylor, R.W., Prokisch, H., and Minczuk, M.

Abstract

Contains fulltext : 154074.pdf (Publisher’s version ) (Open Access), Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history of exercise intolerance. Mutations in TRMT5 were associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA; this hypomodification was particularly prominent in skeletal muscle. Deficiency of the G37 modification was also detected in human cells subjected to TRMT5 RNAi. The pathogenicity of the detected variants was further confirmed in a heterologous yeast model and by the rescue of the molecular phenotype after re-expression of wild-type TRMT5 cDNA in cells derived from the affected individuals. Our study highlights the importance of post-transcriptional modification of mitochondrial tRNAs for faithful mitochondrial function.

Published
2015

42. Mol Biol Cell

Author

Kolanczyk, M., Pech, M., Zemojte, T., Yamamoto, H., Mikula, I., Calvaruso, M., van den Brand, M., Richter, R., Fischer, B., Ritz, A., Kossler, N., Thurisch, B., Spoerle, R., Smeitink, J., Kornak, U., Chan, D., Vingron, M., Martasek, P., Lightowlers, R., Nijtmans, L., Schuelke, M., Nierhaus, K., and Mundlos, S.

Abstract

NOA1 is an evolutionarily conserved GTP binding protein, which localizes predominantly to mitochondria in mammalian cells. Based on bioinformatic analysis we predicted its possible involvement in ribosomal biogenesis, although, this had not been supported by any experimental evidence. Here we determine NOA1 function through generation of knock-out mice and in-vitro assays. NOA1 deficient mice exhibit mid-gestation lethality associated with a severe developmental defect of the embryo and trophoblast. Primary embryonic fibroblasts isolated from NOA1 knock-out embryos show deficient mitochondrial protein synthesis and a global defect of oxidative phosphorylation (OXPHOS). Additionally, Noa1-/- cells are impaired in staurosporine induced apoptosis. The analysis of mitochondrial ribosomal subunits from Noa1-/- cells by sucrose gradient centrifugation and Western blotting showed anomalous sedimentation, consistent with a defect in mitochondrial ribosome assembly. Further, in vitro experiments revealed that intrinsic NOA1 GTPase activity was stimulated by bacterial ribosomal constituents. Taken together, our data show that NOA1 is required for mitochondrial protein synthesis, likely due to its yet unidentified role in mitoribosomal biogenesis. Thus, NOA1 is required for such basal mitochondrial functions as ATP synthesis and apoptosis.

Published
2011

44. Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening

Author

Haack, T.B., Gorza, M., Danhauser, K., Mayr, J.A., Haberberger, B., Wieland, T., Kremer, L., Strecker, V., Graf, E., Memari, Y., Ahting, U., Kopajtich, R., Wortmann, S.B., Rodenburg, R.J.T., Kotzaeridou, U., Hoffmann, G.F., Sperl, W., Wittig, I., Wilichowski, E., Schottmann, G., Schuelke, M., Plecko, B., Stephani, U., Strom, T.M., Meitinger, T., Prokisch, H., Freisinger, P., Haack, T.B., Gorza, M., Danhauser, K., Mayr, J.A., Haberberger, B., Wieland, T., Kremer, L., Strecker, V., Graf, E., Memari, Y., Ahting, U., Kopajtich, R., Wortmann, S.B., Rodenburg, R.J.T., Kotzaeridou, U., Hoffmann, G.F., Sperl, W., Wittig, I., Wilichowski, E., Schottmann, G., Schuelke, M., Plecko, B., Stephani, U., Strom, T.M., Meitinger, T., Prokisch, H., and Freisinger, P.

Abstract

Item does not contain fulltext, Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.

Published
2014

49. G.P.195

Author

Beley, C., primary, Schirwis, E., additional, Mouisel, E., additional, Alonso-Martin, S., additional, Rochat, A., additional, Garcia, L., additional, Ferry, A., additional, Relaix, F., additional, Schuelke, M., additional, Le Grand, F., additional, and Amthor, H., additional

Published
2014
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