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1. A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases

Author

Lucie Isoline Pisella, Sara Fernandes, Guilhem Solé, Tanya Stojkovic, Céline Tard, Jean-Baptiste Chanson, Françoise Bouhour, Emmanuelle Salort-Campana, Guillemette Beaudonnet, Louise Debergé, Fanny Duval, Aude-Marie Grapperon, Marion Masingue, Aleksandra Nadaj-Pakleza, Yann Péréon, Frédérique Audic, Anthony Behin, Diane Friedman, Armelle Magot, Jean-Baptiste Noury, Sarah Souvannanorath, Karim Wahbi, Jean-Christophe Antoine, Kévin Bigaut, Jean-Philippe Camdessanché, Pascal Cintas, Rabab Debs, Caroline Espil-Taris, Laurent Kremer, Thierry Kuntzer, Pascal Laforêt, Vincent Laugel, Martial Mallaret, Maud Michaud, Sylvain Nollet, Juliette Svahn, Savine Vicart, Rocio Nur Villar-Quiles, Isabelle Desguerre, David Adams, Sandrine Segovia-Kueny, Géraldine Merret, Elhadi Hammouda, Annamaria Molon, and Shahram Attarian

Subjects
Neuromuscular diseases, COVID-19, Risk factor, Prognosis, Medicine
Abstract

Abstract Background Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. Results Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. Conclusion During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.

Published
2021
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2. Functional recovery of glycine receptors in spastic murine model of startle disease

Author

Annamaria Molon, Simone Di Giovanni, Yetrib Hathout, JoAnne Natale, and Eric P. Hoffman

Subjects
Glycine receptor, Startle disease, Spasticity, CNS diseases, Excitotoxicity, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Clinical variability is common in inherited gene defects of the central nervous system in humans and in animal models of human disorders. Here, we used the homozygous spastic (spa) mutant mice, which resemble human hereditary hyperekplexia, to determine the molecular remodeling of the spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. The spa mutation is an insertion of a LINE-1 element in the gene for the beta subunit of the glycine receptor, Glrb. The insertion causes aberrant splicing in the beta subunit of glycine receptor gene with a consequent important reduction of glycine receptors. At young ages, all homozygous spa animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the glycine receptor alpha 1 subunit (Glra1), and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express Glra1, and also showed relative loss of gephyrin (receptor clustering). These molecular changes were associated with a preferential loss of GABAergic interneurons, and extensive motorneuron loss. These data suggest that functional recovery is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia show remodeling similar to that of the recovering spa mice, as human patients also show a lessening of symptoms as a function of age.

Published
2006
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3. A National French Consensus on Gene List for the Diagnosis of Charcot–Marie–Tooth Disease and Related Disorders Using Next-Generation Sequencing

Author

Thibaut Benquey, Emmanuelle Pion, Mireille Cossée, Martin Krahn, Tanya Stojkovic, Aurélien Perrin, Mathieu Cerino, Annamaria Molon, Anne-Sophie Lia, Corinne Magdelaine, Bruno Francou, Anne Guiochon-Mantel, Marie-Claire Malinge, Eric Leguern, Nicolas Lévy, Shahram Attarian, Philippe Latour, Nathalie Bonello-Palot, Hospices Civils de Lyon (HCL), Filière Neuromusculaire (FILNEMUS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Limoges, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), MORNET, Dominique, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
next generation sequencing, Consensus, [SDV]Life Sciences [q-bio], public health, High-Throughput Nucleotide Sequencing, rare diseases, Charcot–Marie–Tooth disease, consensus gene list, [SDV] Life Sciences [q-bio], Charcot-Marie-Tooth Disease, Genetics, Humans, Hereditary Sensory and Autonomic Neuropathies, Pathology, Molecular, Genetics (clinical)
Abstract

Next generation sequencing (NGS) is strategically used for genetic diagnosis in patients with Charcot–Marie–Tooth disease (CMT) and related disorders called non-syndromic inherited peripheral neuropathies (NSIPN) in this paper. With over 100 different CMT-associated genes involved and ongoing discoveries, an important interlaboratory diversity of gene panels exists at national and international levels. Here, we present the work of the French National Network for Rare Neuromuscular Diseases (FILNEMUS) genetic diagnosis section which coordinates the seven French diagnosis laboratories using NGS for peripheral neuropathies. This work aimed to establish a unique, simple and accurate gene classification based on literature evidence. In NSIPN, three subgroups were usually distinguished: (1) HMSN, Hereditary Motor Sensory Neuropathy, (2) dHMN, distal Hereditary Motor Neuropathy, and (3) HSAN, Hereditary Sensory Autonomic Neuropathy. First, we reported ClinGen evaluation, and second, for the genes not evaluated yet by ClinGen, we classified them as “definitive” if reported in at least two clinical publications and associated with one report of functional evidence, or “limited” otherwise. In total, we report a unique consensus gene list for NSIPN including the three subgroups with 93 genes definitive and 34 limited, which is a good rate for our gene’s panel for molecular diagnostic use.

Published
2022
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4. A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases

Author

Vincent Laugel, Karim Wahbi, Lucie Isoline Pisella, Rabab Debs, Sarah Souvannanorath, Martial Mallaret, Thierry Kuntzer, Sylvain Nollet, Jean-Christophe Antoine, Maud Michaud, Rocío-Nur Villar-Quiles, Aude-Marie Grapperon, Sandrine Segovia-Kueny, Pascal Laforêt, Céline Tard, EL-Hadi Hammouda, Géraldine Merret, Kévin Bigaut, Juliette Svahn, Laurent Kremer, Armelle Magot, Jean-Baptiste Noury, Guillemette Beaudonnet, Louise Debergé, Aleksandra Nadaj-Pakleza, Diane Friedman, Yann Péréon, Emmanuelle Salort-Campana, Pascal Cintas, Sara Fernandes, David H. Adams, Annamaria Molon, Fanny Duval, Anthony Behin, Shahram Attarian, Frédérique Audic, Jean-Philippe Camdessanché, Isabelle Desguerre, Tanya Stojkovic, Françoise Bouhour, Marion Masingue, Guilhem Solé, Caroline Espil-Taris, Savine Vicart, Jean-Baptiste Chanson, Assistance Publique - Hôpitaux de Marseille (APHM), Groupe hospitalier Pellegrin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Lille, Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), Hôpital Bicêtre, Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Raymond Poincaré [AP-HP], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Henri Mondor [Créteil], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Lausanne University Hospital, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Necker - Enfants Malades [AP-HP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Association française contre les myopathies (AFM-Téléthon), Admin, Oskar, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]

Subjects
medicine.medical_specialty, Cross-sectional study, Population, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Health care, medicine, Humans, Pharmacology (medical), Risk factor, education, Myopathy, Pandemics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, SARS-CoV-2, Research, COVID-19, General Medicine, medicine.disease, Prognosis, Myasthenia gravis, 3. Good health, Neuromuscular diseases, Cross-Sectional Studies, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cohort, Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Background Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. Results Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. Conclusion During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.

Published
2021
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5. A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing

Author

Céline Bouchet-Séraphin, John Rendu, Cécile Acquaviva-Bourdain, Mathieu Cerino, Aurélien Perrin, Frédérique Audic, Jon Andoni Urtizberea, Julien Fauré, Roseline Froissart, Mireille Cossée, Martin Krahn, Corinne Metay, Laurence Michel-Calemard, Damien Sternberg, Judith Melki, Jean Pouget, Emmanuelle Campana-Salort, Nathalie Seta, Annamaria Molon, Juliette Nectoux, François Petit, Valérie Biancalana, Brigitte Chabrol, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de biologie et pathologie Est, Hospices Civils de Lyon (HCL), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal [CHU Lyon] (Centre de Biologie et Pathologie Est), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est, Hôpital de la Timone [CHU - APHM] (TIMONE), Filière Neuromusculaire (FILNEMUS), Service de Neurologie Pédiatrique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des maladies neuromusculaires et de la SLA, Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon (HCL)-Centre National de Référence des Légionelles, Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biochimie Métabolique et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Pitié-Salpêtrière [AP-HP], Astrophysique Interprétation Modélisation (AIM (UMR_7158 / UMR_E_9005 / UM_112)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Astrophysique Interprétation Modélisation (AIM (UMR7158 / UMR_E_9005 / UM_112))

Subjects
Consensus, [SDV]Life Sciences [q-bio], MEDLINE, Computational biology, Biology, DNA sequencing, Article, 03 medical and health sciences, Gene panel, Genetics, Humans, Genetic Testing, Gene, Genetics (clinical), Societies, Medical, 0303 health sciences, Genetic heterogeneity, 030305 genetics & heredity, Neuromuscular Diseases, Sequence Analysis, DNA, Diagnostic strategy, 3. Good health, Practice Guidelines as Topic, France, Genetic diagnosis, Core gene
Abstract

International audience; Next-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies. The strategy is based on the determination of 13 clinical and/or histological entry-diagnosis groups, and consists for each group either in a successive NGS analysis of a "core gene list" followed in case of a negative result by the analysis of an "exhaustive gene list", or in the NGS analysis of a "unique exhaustive gene list".

Published
2019
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6. Reconstitution of the type-1 active site of the H145G/A variants of nitrite reductase by ligand insertion

Author

Annamaria Molon, Hein J. Wijma, Martin Ph. Verbeet, Maria Fittipaldi, Gerard W. Canters, Martin J. Boulanger, Michael E. P. Murphy, Martina Huber, and Biotechnology

Subjects
Alanine, chemistry.chemical_classification, Alcaligenes faecalis, biology, Ligand, Stereochemistry, SPECTROSCOPIC CHARACTERIZATION, Active site, ANGSTROM RESOLUTION, PH VALUES, Nitrite reductase, biology.organism_classification, CRYSTAL-STRUCTURE ANALYSIS, Biochemistry, Redox, BLUE COPPER PROTEINS, X-RAY STRUCTURE, chemistry, Oxidoreductase, biology.protein, ACHROMOBACTER-CYCLOCLASTES, INTRAMOLECULAR ELECTRON-TRANSFER, ALCALIGENES-FAECALIS S-6, PSEUDOMONAS-AERUGINOSA AZURIN, Histidine
Abstract

Variants of the copper-containing nitrite reductase (NiR) of Alcaligenes faecalis S6 were constructed by site-directed mutagenesis, by which the C-terminal histidine ligand (His145) of the Cu in the type-1 site was replaced by an alanine or a glycine. The type-1 sites in the NiR variants as isolated, are in the reduced form, but can be oxidized in the presence of external ligands, like (substituted) imidazoles and chloride. The reduction potential of the type-1 site of NiR-H145A reconstituted with imidazole amounts to 505 mV vs NHE (20degreesC, pH 7, 10 mM imidazole), while for the native type-1 site it amounts to 260 mV. XRD data on crystals of the reduced and oxidized NiR-H145A variant show that in the reduced type-1 site the metal is 3-coordinated, but in the oxidized form takes up a ligand from the solution. With the fourth (exogenous) ligand in place the type-1 site is able to accept electrons at about the same rate as the wt NiR, but it is unable to pass the electron onto the type-2 site, leading to loss of enzymatic activity. It is argued that the uptake of an electron by the mutated type-1 site is accompanied by a loss of the exogenous ligand and a concomitant rise of the redox potential. This rise effectively traps the electron in the type-1 site.

Published
2003

7. Novel spastin mutations and their expression analysis in two Italian families

Author

Corrado Angelini, Elena Pegoraro, Annamaria Molon, and Pasquale Montagna

Subjects
Spastin, Mutant, DNA Mutational Analysis, Mutation, Missense, Gene Expression, Biology, Genetics, Missense mutation, Humans, Allele, Frameshift Mutation, Gene, Genetics (clinical), Alleles, Polymorphism, Single-Stranded Conformational, Dominance (genetics), DNA Primers, Adenosine Triphosphatases, Reverse Transcriptase Polymerase Chain Reaction, RNA, Single-strand conformation polymorphism, Italy, Paraparesis, Spastic, Laminin
Abstract

Mutations in spastin cause the most common form of pure autosomal dominant hereditary spastic paraparesis (SPG4). Here, we report two Italian families affected with SPG4-linked HSP harboring two novel spastin mutations. SSCP/sequencing analysis of the spastin gene showed a single base pair deletion causing a frame-shift in one family (1442delT) and a missense mutation (1726T>C) resulting in a leucine to proline amino-acid change (L534P) in the other family. Total RNA from the mutant and the wild-type spastin allele in muscle biopsies from patients from the two affected families was quantitated. RNA expression was almost absent from the spastin allele harboring the single base pair deletion, while it was nearly normal for the spastin allele harboring the missense mutation. These data suggest that varying spastin RNA levels are found in out-of-frame and missense spastin mutations and imply different mechanisms involved in the molecular pathology of SPG4 linked HSP.

Published
2003

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