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2 results on '"Sands, T. T."'

1. A Novel Kv7.3 Variant in the Voltage-Sensing S4 Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and in vitro Rescue by β-Hydroxybutyrate

Author

Francesco Miceli, Lidia Carotenuto, Vincenzo Barrese, Maria Virginia Soldovieri, Erin L. Heinzen, Arthur M. Mandel, Natalie Lippa, Louise Bier, David B. Goldstein, Edward C. Cooper, Maria Roberta Cilio, Maurizio Taglialatela, Tristan T. Sands, Miceli, F., Carotenuto, L., Barrese, V., Soldovieri, M. V., Heinzen, E. L., Mandel, A. M., Lippa, N., Bier, L., Goldstein, D. B., Cooper, E. C., Cilio, M. R., Taglialatela, M., and Sands, T. T.

Subjects
0301 basic medicine, Physiology, Biology, lcsh:Physiology, Loss of heterozygosity, 03 medical and health sciences, KCNQ, 0302 clinical medicine, Physiology (medical), Missense mutation, Homomeric, BFNE, channelopathies, encephalopathy, ketogenic diet, Exome sequencing, Genetics, lcsh:QP1-981, Genetic heterogeneity, Chinese hamster ovary cell, channelopathie, Phenotype, Transmembrane domain, 030104 developmental biology, 030217 neurology & neurosurgery
Abstract

Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early−onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early−onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE and KCNQ3 variants are responsible for a much smaller subgroup, but the reasons for this imbalance remain unclear. Analysis of additional pedigrees is needed to further clarify the nature of this genetic heterogeneity and to improve prediction of pathogenicity for novel variants. We identified a BFNE family with two siblings and a parent affected. Exome sequencing on samples from both parents and siblings revealed a novel KCNQ3 variant (c.719T>G; p.M240R), segregating in the three affected individuals. The M240 residue is conserved among human Kv7.2-5 and lies between the two arginines (R5 and R6) closest to the intracellular side of the voltage-sensing S4 transmembrane segment. Whole cell patch-clamp recordings in Chinese hamster ovary (CHO) cells revealed that homomeric Kv7.3 M240R channels were not functional, whereas heteromeric channels incorporating Kv7.3 M240R mutant subunits with Kv7.2 and Kv7.3 displayed a depolarizing shift of about 10 mV in activation gating. Molecular modeling results suggested that the M240R substitution preferentially stabilized the resting state and possibly destabilized the activated state of the Kv7.3 subunits, a result consistent with functional data. Exposure to β-hydroxybutyrate (BHB), a ketone body generated during the ketogenic diet (KD), reversed channel dysfunction induced by the M240R variant. In conclusion, we describe the first missense loss-of-function (LoF) pathogenic variant within the S4 segment of Kv7.3 identified in patients with BFNE. Studied under conditions mimicking heterozygosity, the M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density. Our pharmacological results provide a rationale for the use of KD in patients carrying LoF variants in Kv7.2 or Kv7.3 subunits.

Published
2020

2. Autism and developmental disability caused by KCNQ3 gain-of-function variants

Author

Kavita Thakkar, François Rivier, Bitten Schönewolf-Greulich, Gaetan Lesca, Christine Francannet, Nicholas Stong, Sarah Weckhuysen, Vandana Shashi, Marjolaine Willems, Zeynep Tümer, David Goldstein, Daniel K. Arrington, Eric H. Kossoff, Anita E. Beck, Maria Virginia Soldovieri, Erin L. Heinzen, Edward C. Cooper, A. James Barkovich, Heather C Mefford, Francesco Miceli, Lynette G. Sadleir, Tristan T. Sands, Anna Lauritano, Amber Stocco, Ingrid E. Scheffer, Anne Marie Bisgaard, Ana Grijalvo Perez, Deepa S. Rajan, M. Roberta Cilio, Piera Nappi, Bénédicte Gérard, Sébastien Moutton, Maurizio Taglialatela, Antonio Vitobello, Jennifer A. Sullivan, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service de neurologie pédiatrique, Sands, T. T., Miceli, F., Lesca, G., Beck, A. E., Sadleir, L. G., Arrington, D. K., Schonewolf-Greulich, B., Moutton, S., Lauritano, A., Nappi, P., Soldovieri, M. V., Scheffer, I. E., Mefford, H. C., Stong, N., Heinzen, E. L., Goldstein, D. B., Perez, A. G., Kossoff, E. H., Stocco, A., Sullivan, J. A., Shashi, V., Gerard, B., Francannet, C., Bisgaard, A. -M., Tumer, Z., Willems, M., Rivier, F., Vitobello, A., Thakkar, K., Rajan, D. S., Barkovich, A. J., Weckhuysen, S., Cooper, E. C., Taglialatela, M., Cilio, M. R., Columbia University Medical Center (CUMC), Columbia University [New York], 'Federico II' University of Naples Medical School, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University of Washington, Seattle, WA, USA., University of Otago [Dunedin, Nouvelle-Zélande], St. Luke's Children's Hospital, Department of Paediatrics and Adolescent Medicine, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Neuroscience, University of Naples 'Federico II,' Naples, Italy., University of Molise, Epilepsy Research Centre, University of Melbourne, University of Washington, Columbia University Irving Medical Center (CUIMC), University of California [San Francisco] (UCSF), University of California, Johns Hopkins University School of Medicine [Baltimore], INTEGRIS Baptist Medical Center, School of Irish, Celtic Studies, Irish Folklore and Linguistics, University College Dublin [Dublin] (UCD), Duke University [Durham], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, Rigshospitalet [Copenhagen], Copenhagen University Hospital, Clinical genetic clinic, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Hospices Civils de Lyon (HCL), Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], 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 Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Antwerp, Antwerp, Belgium., Baylor College of Medecine, Section of Pharmacology, Università degli studi di Napoli Federico II, University of Naples 'Federico II,', University of Louvain, MORNET, Dominique, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli Studi del Molise = University of Molise (UNIMOL), Department of Pediatrics [Seattle], University of California [San Francisco] (UC San Francisco), University of California (UC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, University of Antwerp (UA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Developmental Disabilities, [SDV]Life Sciences [q-bio], Encephalopathy, Electroencephalography, Protein Structure, Secondary, KCNQ3 Potassium Channel, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, medicine, Humans, Global developmental delay, Amino Acid Sequence, Young adult, Autistic Disorder, Child, ComputingMilieux_MISCELLANEOUS, medicine.diagnostic_test, business.industry, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Clinical research, Neurology, Autism spectrum disorder, Child, Preschool, Gain of Function Mutation, Autism, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract

Objective Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. Methods Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. Results Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. Interpretation Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192

Published
2019

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