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1دورية أكاديمية
المؤلفون: Rebecca Truty, Nila Patil, Raman Sankar, Joseph Sullivan, John Millichap, Gemma Carvill, Ali Entezam, Edward D. Esplin, Amy Fuller, Michelle Hogue, Britt Johnson, Amirah Khouzam, Yuya Kobayashi, Rachel Lewis, Keith Nykamp, Darlene Riethmaier, Jody Westbrook, Michelle Zeman, Robert L. Nussbaum, Swaroop Aradhya
المصدر: Epilepsia Open, Vol 4, Iss 3, Pp 397-408 (2019)
مصطلحات موضوعية: diagnostic genetic testing, next‐generation sequencing panel, copy number variant, precision medicine, clinical management, variant of uncertain significance, Neurology. Diseases of the nervous system, RC346-429
الوصف: Abstract Objective Molecular genetic etiologies in epilepsy have become better understood in recent years, creating important opportunities for precision medicine. Building on these advances, detailed studies of the complexities and outcomes of genetic testing for epilepsy can provide useful insights that inform and refine diagnostic approaches and illuminate the potential for precision medicine in epilepsy. Methods We used a multi‐gene next‐generation sequencing (NGS) panel with simultaneous sequence and exonic copy number variant detection to investigate up to 183 epilepsy‐related genes in 9769 individuals. Clinical variant interpretation was performed using a semi‐quantitative scoring system based on existing professional practice guidelines. Results Molecular genetic testing provided a diagnosis in 14.9%‐24.4% of individuals with epilepsy, depending on the NGS panel used. More than half of these diagnoses were in children younger than 5 years. Notably, the testing had possible precision medicine implications in 33% of individuals who received definitive diagnostic results. Only 30 genes provided 80% of molecular diagnoses. While most clinically significant findings were single‐nucleotide variants, ~15% were other types that are often challenging to detect with traditional methods. In addition to clinically significant variants, there were many others that initially had uncertain significance; reclassification of 1612 such variants with parental testing or other evidence contributed to 18.5% of diagnostic results overall and 6.1% of results with precision medicine implications. Significance Using an NGS gene panel with key high‐yield genes and robust analytic sensitivity as a first‐tier test early in the diagnostic process, especially for children younger than 5 years, can possibly enable precision medicine approaches in a significant number of individuals with epilepsy.
وصف الملف: electronic resource
Relation: https://doaj.org/toc/2470-9239
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المؤلفون: Elisabeth Bosch, Bernt Popp, Esther Güse, Cindy Skinner, Pleuntje J. van der Sluijs, Isabelle Maystadt, Anna Maria Pinto, Alessandra Renieri, Lucia Pia Bruno, Stefania Granata, Carlo Marcelis, Özlem Baysal, Dewi Hartwich, Laura Holthöfer, Bertrand Isidor, Benjamin Cogne, Dagmar Wieczorek, Valeria Capra, Marcello Scala, Patrizia De Marco, Marzia Ognibene, Rami Abou Jamra, Konrad Platzer, Lauren B. Carter, Outi Kuismin, Arie van Haeringen, Reza Maroofian, Irene Valenzuela, Ivon Cuscò, Julian A. Martinez-Agosto, Ahna M. Rabani, Heather C. Mefford, Elaine M. Pereira, Charlotte Close, Kwame Anyane-Yeboa, Mallory Wagner, Mark C. Hannibal, Pia Zacher, Isabelle Thiffault, Gea Beunders, Muhammad Umair, Priya T. Bhola, Erin McGinnis, John Millichap, Jiddeke M van de Kamp, Eloise J. Prijoles, Amy Dobson, Amelle Shillington, Brett H. Graham, Evan-Jacob Garcia, Maureen Kelly Galindo, Fabienne G. Ropers, Esther AR Nibbeling, Gail Hubbard, Catherine Karimov, Guido Goj, Renee Bend, Julie Rath, Michelle M Morrow, Francisca Millan, Vincenzo Salpietro, Annalaura Torella, Vincenzo Nigro, Mitja Kurki, Roger E Stevenson, Gijs W.E. Santen, Markus Zweier, Philippe M. Campeau, Mariasavina Severino, André Reis, Andrea Accogli, Georgia Vasileiou
الوصف: PURPOSECoffin-Siris and Nicolaides-Baraitser syndromes, are recognisable neurodevelopmental disorders caused by germline variants in BAF complex subunits. TheSMARCC2BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.METHODSClinical symptoms for 41 novel and 24 previously published cases were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlation, molecular data were standardized and grouped into non-truncating and likely gene-disrupting variants (LGD). Missense variant protein expression and BAF subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.RESULTSNeurodevelopmental delay with intellectual disability, muscular hypotonia and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, while non-truncating variants were mostlyde novoand presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms.In vitrotesting showed decreased protein expression for N-terminal missense variants similar to LGD.CONCLUSIONThis study improvedSMARCC2variant classification and identified discernibleSMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::c27085d1605a13771b0976056173917e
https://doi.org/10.1101/2023.03.30.23287962 -
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المؤلفون: Dennis J. Dlugos, Jacqueline A. French, Cynthia L. Harden, Simon N. Pimstone, Noam Butterfield, Celene Grayson, Ernesto Aycardi, John Millichap
المصدر: Epilepsia Open
Epilepsia Open, Vol 6, Iss 1, Pp 38-44 (2021)مصطلحات موضوعية: Pediatrics, medicine.medical_specialty, Video Recording, Electroencephalography, lcsh:RC346-429, Food and drug administration, Epilepsy, Seizure diary, Treatment trial, Seizures, medicine, Humans, KCNQ2 Potassium Channel, In patient, Prospective Studies, Critical Reviews, lcsh:Neurology. Diseases of the nervous system, KCNQ2, Pediatric epilepsy, Brain Diseases, Clinical Trials as Topic, medicine.diagnostic_test, business.industry, tonic seizures, Infant, Newborn, Infant, Critical Review, medicine.disease, United States, Diaries as Topic, Clinical trial, seizure diaries, Neurology, epilepsy, video‐EEG, Neurology (clinical), business, Epileptic Syndromes
الوصف: Literature review of patients with KCNQ2 developmental and epileptic encephalopathy (KCNQ2‐DEE) reveals, based on 16 reports including 139 patients, a clinical phenotype that includes age‐ and disease‐specific stereotyped seizures. The typical seizure type of KCNQ2‐DEE, focal tonic, starts within 0‐5 days of life and is readily captured by video‐electroencephalography VEEG for clinical and genetic diagnosis. After initial identification, KCNQ2‐DEE seizures are clinically apparent and can be clearly identified without the use of EEG or VEEG. Therefore, we propose that the 2019 recommendations from the International League against Epilepsy (ILAE), the Pediatric Epilepsy Research Consortium (PERC), for capturing and recording seizures for clinical trials (Epilepsia Open, 4, 2019, 537) are suitable for use in KCNQ2‐DEE‒associated antiseizure medicine (ASM) treatment trials. The ILAE/PERC consensus guidance states that a caregiver‐maintained seizure diary, completed by caregivers who are trained to recognize seizures using within‐patient historical recordings, accurately captures seizures prospectively in a clinical trial. An alternative approach historically endorsed by the Food and Drug Administration (FDA) compares seizure counts captured on VEEG before and after treatment. A major advantage of the ILAE/PERC strategy is that it expands the numbers of eligible patients who meet inclusion criteria of clinical trials while maintaining accurate seizure counts (Epilepsia Open, 4, 2019, 537). Three recent phase 3 pivotal pediatric trials investigating ASMs to treat syndromic seizures in patients as young as 2 years of age (N Engl J Med, 17, 2017, 699; Lancet, 21, 2020, 2243; Lancet, 17, 2018, 1085); and ongoing phase 2 open‐label pediatric clinical trial that includes pediatric epileptic syndromes as young as 1 month of age (Am J Med Genet A, 176, 2018, 773), have already used caregiver‐maintained seizure diaries successfully. For determining the outcome of a KCNQ2‐DEE ASM treatment trial, the use of a seizure diary to count seizures by trained observers is feasible because the seizures of KCNQ2‐DEE are clinically apparent. This strategy is supported by successful precedent in clinical trials in similar age groups and has the endorsement of the international pediatric epilepsy community.
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المؤلفون: Tatiana Abramova, Christopher H. Thompson, Alfred L. George, John Millichap, Jean Marc DeKeyser, Scott K. Adney
المصدر: Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology, Vol 7, Iss 9, Pp 1488-1501 (2020)مصطلحات موضوعية: 0301 basic medicine, Male, Heterologous, Neurosciences. Biological psychiatry. Neuropsychiatry, Pharmacology, law.invention, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Sodium channel blocker, law, Genotype, Medicine, Humans, Patch clamp, Age of Onset, RC346-429, Genetic Association Studies, Research Articles, NAV1.2 Voltage-Gated Sodium Channel, business.industry, General Neuroscience, Infant, Carbamazepine, medicine.disease, Phenotype, Electrophysiological Phenomena, 030104 developmental biology, Recombinant DNA, Anticonvulsants, Neurology. Diseases of the nervous system, Neurology (clinical), business, 030217 neurology & neurosurgery, RC321-571, medicine.drug, Research Article
الوصف: Objective We identified a novel de novo SCN2A variant (M1879T) associated with infantile‐onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response. Methods The clinical and genetic features of an infant boy with epilepsy are presented. We investigated the effect of the variant using heterologously expressed recombinant human NaV1.2 channels. We performed whole‐cell patch clamp recording to determine the functional consequences and response to carbamazepine. Results The M1879T variant caused disturbances in channel inactivation including substantially depolarized voltage dependence of inactivation, slower time course of inactivation, and enhanced resurgent current that collectively represent a gain‐of‐function. Carbamazepine partially normalized the voltage dependence of inactivation and produced use‐dependent block of the variant channel at high pulsing frequencies. Carbamazepine also suppresses resurgent current conducted by M1879T channels, but this effect was explained primarily by reducing the peak transient current. Molecular modeling suggests that the M1879T variant disrupts contacts with nearby residues in the C‐terminal domain of the channel. Interpretation Our study demonstrates the value of conducting functional analyses of SCN2A variants of unknown significance to establish pathogenicity and genotype–phenotype correlations. We also show concordance of in vitro pharmacology using heterologous cells with the drug response observed clinically in a case of SCN2A‐associated epilepsy.
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المؤلفون: Robert A. Hegele, Maria Iascone, Kevin A. Shapiro, Nicolas Chatron, Marwan Shinawi, Joel Charrow, Jeffrey W. Innis, Luitgard Graul-Neumann, Joanna Goes Castro Meira, Anna Lehman, Dawn L. Earl, Victoria R. Sanders, Shannon Rego, David A. Sweetser, Clémantine Dimartino, Wilhelmina S. Kerstjens-Frederikse, Antonio Vitobello, Davor Lessel, Daniel Grinberg, Laurence Faivre, Ryan Peretz, Katherine M. Christensen, Emma Reesor, Erin Beaver, Elizabeth Wohler, Margot R.F. Reijnders, Deborah Barbouth, Anna Cereda, Kaja Kristine Selmer, Melissa A. Walker, Barbro Stadheim, Alessandro Serretti, Helen Kingston, Jill Clayton-Smith, Raymond Lewandowski, Bernarda Lozić, Robert Stratton, Amelia Kirby, Anne H. O’Donnell-Luria, Sara Gabbiadini, Susanna Balcells, Myriam Oufadem, Christel Thauvin, Maha Aly, Wendy K. Chung, Susan M. White, Lauren C. Briere, Thomas Smol, Stanislas Lyonnet, Roberto Colombo, Catherine E. Keegan, Marie T. McDonald, Melanie Parisot, Tiong Yang Tan, Brian Wong, Christopher T. Gordon, Magnus Dehli Vigeland, Frances A. High, Emily Bryant, Audrey Labalme, Nara Sobreira, Arnold Munnich, Jeanne Amiel, Dayna Morel Swols, Raquel Rabionet, Laura Castilla-Vallmanya, Jennifer Heeley, Gunnar Houge, Michael J. Gambello, Bernardo Blanco-Sánchez, Lynn Pais, Olena M. Vaske, Roser Urreizti, Alison Wray, Veronique Pingault, Damien Sanlaville, John Christodoulou, John Millichap, Valérie Cormier-Daire, Parul Jayakar, Helen Cox, Frédéric Tran Mau-Them, Belinda Chong, Victoria Mok Siu, Anne Slavotinek, Antonie J. van Essen, Ingvild Aukrust, Lorne A. Clarke, Rachel Gannaway, Anne Dieux-Coeslier, Patrick Nitschké, Tony Yao, Simon Sadedin, Danielle Karlowicz, Christelle Rougeot, Christine Bole-Feysot, Sandra Yang, Megan T. Cho, Gaetan Lesca, Christiane Zweier
المساهمون: Castilla-Vallmanya L., Selmer K.K., Dimartino C., Rabionet R., Blanco-Sanchez B., Yang S., Reijnders M.R.F., van Essen A.J., Oufadem M., Vigeland M.D., Stadheim B., Houge G., Cox H., Kingston H., Clayton-Smith J., Innis J.W., Iascone M., Cereda A., Gabbiadini S., Chung W.K., Sanders V., Charrow J., Bryant E., Millichap J., Vitobello A., Thauvin C., Mau-Them F.T., Faivre L., Lesca G., Labalme A., Rougeot C., Chatron N., Sanlaville D., Christensen K.M., Kirby A., Lewandowski R., Gannaway R., Aly M., Lehman A., Clarke L., Graul-Neumann L., Zweier C., Lessel D., Lozic B., Aukrust I., Peretz R., Stratton R., Smol T., Dieux-Coeslier A., Meira J., Wohler E., Sobreira N., Beaver E.M., Heeley J., Briere L.C., High F.A., Sweetser D.A., Walker M.A., Keegan C.E., Jayakar P., Shinawi M., Kerstjens-Frederikse W.S., Earl D.L., Siu V.M., Reesor E., Yao T., Hegele R.A., Vaske O.M., Rego S., Shapiro K.A., Wong B., Gambello M.J., McDonald M., Karlowicz D., Colombo R., Serretti A., Pais L., O'Donnell-Luria A., Wray A., Sadedin S., Chong B., Tan T.Y., Christodoulou J., White S.M., Slavotinek A., Barbouth D., Morel Swols D., Parisot M., Bole-Feysot C., Nitschke P., Pingault V., Munnich A., Cho M.T., Cormier-Daire V., Balcells S., Lyonnet S., Grinberg D., Amiel J., Urreizti R., Gordon C.T., MUMC+: DA KG Polikliniek (9), RS: FHML non-thematic output
المصدر: Dipòsit Digital de la UB
Universidad de Barcelona
Genetics in Medicine, 22(7), 1215-1226. Nature Publishing Group
Genet Medمصطلحات موضوعية: 0301 basic medicine, NF-KAPPA-B, PROTEIN, 030105 genetics & heredity, medicine.disease_cause, Germline, Transcriptome, ACTIVATION, POLYUBIQUITINATION, Missense mutation, Exome, Genetics (clinical), Genetics, Sanger sequencing, Mutation, leads, Necrosi, craniofacial development, Phenotype, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, intellectual disability, patent ductus arteriosu, symbols, Mutation, Missense, Biology, traf7, Article, akt1, target, 03 medical and health sciences, symbols.namesake, Necrosis, patent ductus arteriosus, medicine, Humans, blepharophimosi, Tumors, MUTATIONS, Fibroblasts, medicine.disease, Blepharophimosis, TRAF7, blepharophimosis, GENOMIC ANALYSIS, Germ Cells, 030104 developmental biology, MENINGIOMAS
الوصف: PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
وصف الملف: STAMPA; application/pdf
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المؤلفون: Gemma L. Carvill, Jacqueline J Wolak, Joel Charrow, Christopher Miller, Emily Bryant, Victoria R. Sanders, Jeffrey D. Calhoun, Jessica Giannelli, John Millichap, Egidio Spinelli
المصدر: American Journal of Medical Genetics Part A. 182:1460-1465
مصطلحات موضوعية: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Microcephaly, Glycosylation, Protein subunit, 030105 genetics & heredity, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, Genetics, medicine, Genetics (clinical), chemistry.chemical_classification, business.industry, medicine.disease, Phenotype, carbohydrates (lipids), 030104 developmental biology, Endocrinology, chemistry, Oligosaccharyltransferase complex, Transferrin, Dysplasia, lipids (amino acids, peptides, and proteins), business, Congenital disorder of glycosylation
الوصف: Congenital disorders of glycosylation (CDG) are metabolic disorders that affect the glycosylation of proteins and lipids. Since glycosylation affects all organs, CDG show a wide spectrum of phenotypes. We present a patient with microcephaly, dysmorphic facies, congenital heart defect, focal epilepsy, infantile spasms, skeletal dysplasia, and a type 1 serum transferrin isoelectrofocusing due to a novel CDG caused by a homozygous variant in the oligosaccharyltransferase complex noncatalytic subunit (OSTC) gene involved in glycosylation and confirmed by serum transferrin electrophoresis.
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المؤلفون: Josep Dalmau, Bradford B. Worrall, Olga Ciccarelli, Jonathan W. Mink, Anthony A. Amato, John R. Corboy, Robert A. Gross, Ryan J. Uitti, John Millichap, Rebecca F. Gottesman, Stefan M. Pulst, Murray Grossman, Gregory D. Cascino
المصدر: Neurology. 94:3-11
مصطلحات موضوعية: Medical education, business.industry, Scientific writing, Section (typography), Confidentiality, Neurology (clinical), Neurologic disease, business, Psychology, Turnaround time, Publication, Constructive, Patient care
الوصف: From April 1, 2011, through September 30, 2011, Neurology ® received 2,167 new and 643 revised manuscripts. During this interval, 3,909 peer reviews were received (compared to 3,758 during the same period in 2010), with the average turnaround time after assignment being 8.5 days. Average time from submission to first decision for papers chosen for review remained at 33 days. Limitations in the number of pages we can publish allow us to accept only a minority of papers submitted. Your specific comments regarding the uniqueness of study populations, novel methods, studies that are especially educational, or new strategies for diagnosing and treating neurologic disease are appreciated; these comments help us immeasurably when we make final decisions regarding which articles we believe will most benefit our authors and readers, as well as improve patient care. Manuscripts for the Resident & Fellow Section of Neurology are often submitted by trainees who have less experience in preparing articles for publication, and it is the goal of the Section to help these junior authors improve their clinical and scientific writing abilities. We especially appreciate the constructive feedback provided by reviewers of these manuscripts. We recently posted an Information for Reviewers (IFR) link on www.neurology.org. Click on this link for information on expectations of reviewers regarding confidentiality, timeliness, and reviewer conflicts of interest. The IFR also provides instructions for formatting the comments to editors and authors in order to make communication with authors most effective. In appreciation of your dedication to Neurology , we offer an hour of CME credit, if requested, for each manuscript you review for the Journal (maximum of 15 credits per year as determined by ACCME). To receive credit, it should be evident that the reviewer has read and understood the content of the manuscript, accompanying figures and tables, supplementary …
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1ede3ac23adc4e52889dda011a1de02e
https://doi.org/10.1212/wnl.0000000000008689 -
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المؤلفون: Paula Goldenberg, Jeffrey D. Calhoun, Eyby Leon, Sunita N. Misra, Ethan M. Goldberg, Carlos G. Vanoye, Isabelle Thiffault, Kevin A. Strauss, Jennifer A. Kearney, Neil R. Friedman, Ali Torkamani, John Millichap, Jasper J. van der Smagt, Lauren E. Grote, Mark C. Hannibal, Katarina L. Fabre, Dennis M. Echevarria, Robert P. Carson, Dianalee McKnight, Jullianne Diaz, Jessica Litwin, Bryan Lynch, Annapurna Poduri, John B. O’Connor, Eric D. Marsh, Alfred L. George, Carol J. Saunders, Allison Schreiber, Joseph E. Jacher, Laurie A. Demmer, Koen L.I. van Gassen, Seok Kyu Kang
المصدر: Annals of Neurology. 86:899-912
مصطلحات موضوعية: 0301 basic medicine, Mechanism (biology), Chinese hamster ovary cell, Heterologous, Biology, biology.organism_classification, Potassium channel, Cell biology, 03 medical and health sciences, Electrophysiology, 030104 developmental biology, 0302 clinical medicine, Neurology, Neurology (clinical), Cricetulus, Peptide sequence, 030217 neurology & neurosurgery, Function (biology)
الوصف: Objective Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. Methods We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. Results Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. Interpretation Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.
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المؤلفون: Elizabeth Roeder, Simone Mandelstam, Alicia Guemez-Gamboa, Ingrid E. Scheffer, Satoko Kumada, Emily Bryant, Lance H. Rodan, Berkley Schmidt, Jessica Giannelli, Kyle R Christensen, Kirsty McWalter, Kazuhiro Iwama, John Millichap, Alison M. Muir, Egidio Spinelli, Tiziano Pisano, Heather C Mefford, Linda Laux, Renzo Guerrini, Eva H. Brilstra, Rebecca O. Littlejohn, Amy L Schneider, Carmen Barba, Gemma L. Carvill, Naomichi Matsumoto, Elysa J. Marco, Angus C. Nairn, William G. Wilson, Jennifer Rakotomamonjy, Richard H. van Jaarsveld
مصطلحات موضوعية: Genetics, Epilepsy, Neurodevelopmental disorder, HEK 293 cells, medicine, Missense mutation, Transfection, Biology, Corpus callosum, medicine.disease, Gene, Exome sequencing
الوصف: ObjectiveThe MAST family of microtubule-associated serine-threonine kinases (STK) have distinct expression patterns in the developing and mature human and mouse brain. To date, only MAST1 has been associated with neurological disease, with de novo variants in individuals with a neurodevelopmental disorder, including a mega corpus callosum.MethodsUsing exome sequencing we identify MAST3 missense variants in individuals with epilepsy. We also assess the effect of these variants on the ability of MAST3 to phosphorylate the target gene product ARPP-16 in HEK293T cells.ResultsWe identify de novo missense variants in the STK domain in 11 individuals, including two recurrent variants p.G510S (n=5) and p.G515S (n=3). All 11 individuals had Developmental and epileptic encephalopathy, with 8 having normal development prior to seizure onset at < 2 years of age. All patients developed multiple seizures types, while 9/11 had seizures triggered by fever and 9/11 had drug-resistant seizures. In vitro analysis of HEK293T cells transfected with MAST3 cDNA carrying a subset of these patient-specific missense variants demonstrated variable but generally lower expression, with concomitant increased phosphorylation of the MAST3 target, ARPP-16, compared to wildtype. These findings suggest the patient-specific variants may confer MAST3 gain-of-function. Moreover, single-nuclei RNA sequencing and immunohistochemistry shows that MAST3 expression is restricted to excitatory neurons in the cortex late in prenatal development and postnatally.InterpretationIn summary, we describe MAST3 as a novel epilepsy-associated gene with a potential gain-of-function pathogenic mechanism that may be primarily restricted to excitatory neurons in the cortex.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_________::32f1eb573df871ce718e8a420d82fdea
https://doi.org/10.1101/2021.03.09.434675 -
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المؤلفون: Christopher H. Thompson, Carlos G. Vanoye, John Millichap, Alfred L. George, Tracy S. Gertler
المصدر: Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology, Vol 6, Iss 9, Pp 1606-1615 (2019)مصطلحات موضوعية: Male, 0301 basic medicine, Proband, Neurosciences. Biological psychiatry. Neuropsychiatry, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Bioinformatics, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Humans, Channel blocker, RC346-429, Child, Research Articles, Dystonia, business.industry, General Neuroscience, Chinese hamster ovary cell, Brain, Infant, medicine.disease, Magnetic Resonance Imaging, Status dystonicus, Potassium channel, 3. Good health, Electrophysiology, Phenotype, 030104 developmental biology, Child, Preschool, Mutation, Neurology. Diseases of the nervous system, Neurology (clinical), business, Spasms, Infantile, 030217 neurology & neurosurgery, RC321-571, Research Article
الوصف: Objective We identified a novel de novo KCNT1 variant in a patient with early‐infantile epileptic encephalopathy (EIEE) and status dystonicus, a life‐threatening movement disorder. We determined the functional consequences of this variant on the encoded KNa1.1 channel to investigate the molecular mechanisms responsible for this disorder. Methods A retrospective case review of the proband is presented. We performed manual and automated electrophysiologic analyses of the KCNT1‐L437F variant expressed heterologously in Chinese hamster ovary (CHO) cells in the presence of channel activators/blockers. Results The KCNT1‐L437F variant, identified in a patient with refractory EIEE and status dystonicus, confers a gain‐of‐function channel phenotype characterized by instantaneous, voltage‐dependent activation. Channel openers do not further increase L437F channel function, suggesting maximal activation, whereas channel blockers similarly block wild‐type and variant channels. We further demonstrated that KCNT1 current can be measured on a high‐throughput automated electrophysiology platform with potential value for future screening of novel and repurposed pharmacotherapies. Interpretation A novel pathogenic variant in KCNT1 associated with early‐onset, medication‐refractory epilepsy and dystonia causes gain‐of‐function with rapid activation kinetics. Our findings extend the genotype–phenotype relationships of KCNT1 variants to include severe dystonia.
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