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1. A novel homozygous truncating variant of NECAP1 in early infantile epileptic encephalopathy: the second case report of EIEE21

Author

Satomi Mitsuhashi, Atsushi Takata, Lip H Moey, Takeshi Mizuguchi, Mitsuko Nakashima, Satoko Miyatake, Noriko Miyake, Hirotomo Saitsu, Naomichi Matsumoto, Gaik S Ch'ng, and Teik-Beng Khoo

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Ohtahara syndrome, Nonsense mutation, 030105 genetics & heredity, Biology, Epileptogenesis, 03 medical and health sciences, Adaptor Protein Complex alpha Subunits, Seizures, Internal medicine, Complementary DNA, Genetics, medicine, Humans, Synaptic vesicle recycling, Genetics (clinical), Messenger RNA, Homozygote, Brain, Infant, medicine.disease, Burst suppression, 030104 developmental biology, Endocrinology, Mutation, RNA splicing, Spasms, Infantile
Abstract

We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.

Published
2019
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2. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Author

Antonio Vitobello, Christel Depienne, Kelly Radtke, Bruria Ben-Zeev, Vaidutis Kučinskas, Hirofumi Kashii, Leslie Granger, Florence Demurger, Adi Vaknin-Dembinsky, Androu Waheeb, Takeshi Mizuguchi, Lip H. Moey, Urania Kotzaeridou, Frédérique Béna, Fernando Kok, Timothy Blake Palculict, Yasmin Hamzavi Abedi, Satoko Miyatake, Anne-Sophie Denommé-Pichon, Linda Manwaring, Laura Elena Orec, Laurens Wiel, Han G. Brunner, Sylvie Odent, Eric Vilain, Linh Tran, Simon E. Fisher, Emmanuèlle C. Délot, Vidya Krishnamurthy, Rebecca C. Spillmann, Hilary Coon, Shelagh Joss, Hui B. Chew, Matias Wagner, David A. Dyment, Kirsty McWalter, Michael W. Parker, Adam Jackson, Margje Sinnema, Pengfei Liu, Elke de Boer, Alma Kuechler, Christoffer Nellåker, Christian Gilissen, Yasuo Hachiya, Marcia C. Willing, Shivarajan M. Amudhavalli, Alexander P.A. Stegmann, Ange-Line Bruel, Siddharth Banka, Joery den Hoed, Vardiella Meiner, Rosalyn Jewell, Britton D Zuccarelli, Alexander J. M. Dingemans, Kelly L. Jones, Anja A. Kattentidt-Mouravieva, Matthew Osmond, Orly Elpeleg, Andrea K. Petersen, Nicolas Guex, Dianne F. Newbury, Jill A. Rosenfeld, Alexandre Reymond, Mohamad A. Mikati, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Naomichi Matsumoto, Vincent R. Bonagura, Loreta Cimbalistienė, Benoît Mazel, Hayley S. Mountford, Isabelle Thiffault, Rolph Pfundt, Ruth Newbury-Ecob, Teresa Santiago-Sim, Alinoë Lavillaureix, Eglė Preikšaitienė, Jacqueline Chrast, Toshiyuki Itai, Norine Voisin, Usha Kini, Emmanuelle Ranza, Caitlin Schwager, Brooke Horist, Samantha A. Schrier Vergano, Jennifer Hanebeck, Juliana H. Vedovato-dos-Santos, Mitsuhiro Kato, Theresa Brunet, Lot Snijders Blok, Jayne Y. Hehir-Kwa, Shehla Mohammed, Benjamin Haber, Hagar Mor-Shaked, Laurence Faivre, Dian Donnai, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Université de Lausanne = University of Lausanne (UNIL), Children's Mercy Hospital [Kansas City], University of Manchester [Manchester], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Radboud University [Nijmegen], Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, University of Lausanne (UNIL), 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), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Radboud university [Nijmegen], The DDD study, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)

Subjects
0301 basic medicine, Male, Models, Molecular, MISSENSE MUTATIONS, CHROMATIN, Transcription, Genetic, Cell, Medizin, Disease, Haploinsufficiency, medicine.disease_cause, 0302 clinical medicine, Missense mutation, de novo variants, Genetics (clinical), INTERLEUKIN-2, seizures, Genetics, 0303 health sciences, Mutation, Chromatin binding, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SATB1, Phenotype, medicine.anatomical_structure, intellectual disability, Female, teeth abnormalities, Protein Binding, Neuroinformatics, EXPRESSION, GENES, Mutation, Missense, Biology, BINDING PROTEIN, REGION, 03 medical and health sciences, Protein Domains, Report, medicine, HPO-based analysis, Humans, Genetic Association Studies, Hpo-based Analysis, Satb1, Cell-based Functional Assays, De Novo Variants, Intellectual Disability, Neurodevelopmental Disorders, Seizures, Teeth Abnormalities, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Matrix Attachment Region Binding Proteins, 030104 developmental biology, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery, cell-based functional assays
Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

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