Emanuela Dazzo1, Kati Rehberg2, Roberto Michelucci3, Daniela Passarelli4, Clementina Boniver5, Valeria Vianello Dri6, Pasquale Striano7, Salvatore Striano8, R Jeroen Pasterkamp2, Carlo Nobile1,9. 1. CNR-Neuroscience Institute, Section of Padua, Padova, Italy. 2. Department of Translational Neuroscience, Brain Center Rudolf Magnus, UMC Utrecht, Utrecht University, Utrecht, The Netherlands. 3. IRCCS-Institute of Neurological Sciences of Bologna, Unit of Neurology, Bellaria Hospital, Bologna, Italy. 4. Division of Neurology, Infermi Hospital, Faenza, Italy. 5. Clinical Neurophysiology, Department of Pediatrics, University of Padua, Padova, Italy. 6. APSS Trento, Mental Health Department, Child and Adolescent Neuropsichiatry 1, Trento, Italy. 7. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy. 8. Department of Neurological Sciences, Federico II University, Napoli, Italy. 9. Department of Biomedical Sciences, University of Padua, Padova, Italy.
Abstract
OBJECTIVE: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. METHODS: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. RESULTS: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. INTERPRETATION: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483-493.
OBJECTIVE: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy characterized by auditory symptoms. Two genes, LGI1 and RELN, encoding secreted proteins, are implicated in the etiology of ADLTE, but half of the affected families remain genetically unsolved, and the underlying molecular mechanisms are yet to be clarified. We aimed to identify additional genes causing ADLTE to better understand the genetic basis and molecular pathway underlying this epileptic disorder. METHODS: A cohort of Italian ADLTE families was examined by whole exome sequencing combined with genome-wide single-nucleotide polymorphism-array linkage analysis. RESULTS: We identified two ADLTE-causing variants in the MICAL-1 gene: a p.Gly150Ser substitution occurring in the enzymatically active monooxygenase (MO) domain and a p.Ala1065fs frameshift indel in the C-terminal domain, which inhibits the oxidoreductase activity of the MO domain. Each variant segregated with ADLTE in a single family. Examination of candidate variants in additional genes excluded their implication in ADLTE. In cell-based assays, both variants significantly increased MICAL-1 oxidoreductase activity and induced cell contraction in COS7 cells, which likely resulted from deregulation of F-actin dynamics. INTERPRETATION: MICAL-1 oxidoreductase activity induces disassembly of actin filaments, thereby regulating the organization of the actin cytoskeleton in developing and adult neurons and in other cell types. This suggests that dysregulation of the actin cytoskeleton dynamics is a likely mechanism by which MICAL-1 pathogenic variants lead to ADLTE. Ann Neurol 2018;83:483-493.
Authors: Alessandro Esposito; Valeria Ventura; Maxim V Petoukhov; Amrita Rai; Dmitri I Svergun; Maria A Vanoni Journal: Protein Sci Date: 2018-10-31 Impact factor: 6.725
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Authors: Klitos Konstantinidis; Vassilios J Bezzerides; Lo Lai; Holly M Isbell; An-Chi Wei; Yuejin Wu; Meera C Viswanathan; Ian D Blum; Jonathan M Granger; Danielle Heims-Waldron; Donghui Zhang; Elizabeth D Luczak; Kevin R Murphy; Fujian Lu; Daniel H Gratz; Bruno Manta; Qiang Wang; Qinchuan Wang; Alex L Kolodkin; Vadim N Gladyshev; Thomas J Hund; William T Pu; Mark N Wu; Anthony Cammarato; Mario A Bianchet; Madeline A Shea; Rodney L Levine; Mark E Anderson Journal: J Clin Invest Date: 2020-09-01 Impact factor: 14.808