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3 results on '"Shannon Sattler"'

1. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author

Benjamin Cogné, Stephen Sanders, François Rivier, Tahir N. Khan, Mireille Claustres, Gaetan Lesca, Lihadh Al-Gazali, Annick Vogels, Sarah Weckhuysen, Nicholas Katsanis, Stéphane Bézieau, Thomas Besnard, Maxime Cadieux-Dion, Julitta de Bellescize, Katrin Õunap, Anne Boland, Aurora Pujol, Monica H. Wojcik, Maria J. Guillen Sacoto, Paul Rollier, Laurent Pasquier, Bertrand Isidor, Sébastien Küry, Hilde Van Esch, Aisha Al Shamsi, Megan T. Cho, Kyle Retterer, Michel Koenig, Christèle Dubourg, Andreas G. Chiocchetti, Damien Sanlaville, Erica E. Davis, Claire Guissart, Sander Pajusalu, Hannah Stamberger, Xenia Latypova, Shannon Sattler, Souphatta Sasorith, Isabelle Thiffault, Marie Vincent, Nicolas Leboucq, Irman Forghani, Lynn Schema, Sylvie Odent, Marie T. McDonald, Lauren E. Grote, Susanne Kjaergaard, Wilfrid Carré, Rena Pressman, Emily G. Farrow, Jean-François Deleuze, Carol J Saunders, Deborah Barbouth, Danielle Karlowicz, Nicole P. Safina, Kirsty McWalter, Christine M. Freitag, Wim Van Paesschen, Rebecca Willaert, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Genetics, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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 génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universitätsklinikum Leipzig, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Human Molecular Genetics, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de biologie moléculaire, Hôpital Pontchaillou, Centre National de Genotypage, Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Pediatrics, Faculty of Medicine and Health Sciences, UAE University, 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), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Génétique, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Center for Human Disease Modeling, Duke University [Durham], Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Service de génétique clinique, hôpital Sud, National Human Genome Research Institute, UM1 HG008900, National Eye Institute, PUT355, Eesti Teadusagentuur, 2011-RARE-004-01, Agence Nationale pour la Recherche/E-rare Joint-Transnational-Call 2011, National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program, R01 MH106826, NIH, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud

Subjects
Male, 0301 basic medicine, Autism, [SDV]Life Sciences [q-bio], Neurodegenerative, Medical and Health Sciences, RORA, Purkinje Cells, 0302 clinical medicine, Neurodevelopmental disorder, Group F, 80 and over, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, Zebrafish, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Genes, Dominant, Pediatric, Genetics & Heredity, Aged, 80 and over, Genetics, Malalties neurodegeneratives, Brain, Nuclear Receptor Subfamily 1, Group F, Member 1, Neurodegenerative Diseases, Syndrome, Biological Sciences, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Mental Health, intellectual disability, Child, Preschool, Larva, Neurological, Female, Cerebellar atrophy, medicine.symptom, Haploinsufficiency, Adult, Member 1, Ataxia, Cerebellar Ataxia, Nuclear Receptor Subfamily 1, Adolescent, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Biology, Article, 03 medical and health sciences, Rare Diseases, medicine, Animals, Humans, Dominant, Autistic Disorder, Allele, Preschool, Alleles, Aged, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cerebellar ataxia, Animal, Point mutation, Genetic Complementation Test, Neurosciences, medicine.disease, neurodevelopmental disorder, Brain Disorders, Disease Models, Animal, 030104 developmental biology, Genes, autistic features, Disease Models, Mutation, epilepsy, Human medicine, cerebellar ataxia, Missense, Autisme, dual molecular effects, 030217 neurology & neurosurgery
Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome. ispartof: American Journal of Human Genetics vol:102 issue:5 pages:744-759 ispartof: location:United States status: published

Published
2018
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2. Gain-of-Function Mutations inRARBCause Intellectual Disability with Progressive Motor Impairment

Author

André Tremblay, Jacques L. Michaud, Nicolas Chassaing, Rebecca O. Littlejohn, Troy A. Becker, Marie Ange Delrue, Shannon Sattler, Véronique Caron, Zoha Kibar, Sarah B. Nielsen, Virginia Kimonis, Elizabeth Roeder, Pierre Bitoun, Sébastien Lévesque, Fan Xia, Toni S. Pearson, Jill A. Rosenfeld, Sofia Douzgou, Fadi F. Hamdan, Sonal Desai, Michael C. Schneider, Myriam Srour, and Adele Schneider

Subjects
0301 basic medicine, Dystonia, medicine.medical_specialty, Retinoic acid, Chorea, Biology, medicine.disease, Microphthalmia, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Endocrinology, chemistry, Internal medicine, Genetics, medicine, Diaphragmatic hernia, Global developmental delay, Spasticity, medicine.symptom, Receptor, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.

Published
2016
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3. De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features

Author

Wendy K. Chung, Volkan Okur, Michael C. Schneider, Lauren Brady, Meron Azage, Jonathan Picker, Sharyn A. Lincoln, Amy Dameron, Dmitriy Niyazov, Carolyn D. Applegate, Berivan Baskin, Mark A. Tarnopolsky, Hans T. Bjornsson, Megan T. Cho, Rebecca Willaert, Jane Juusola, Sharon R. Smith, Shannon Sattler, Kyle Retterer, and Lindsay B. Henderson

Subjects
0301 basic medicine, Microcephaly, Adolescent, Biology, medicine.disease_cause, Bioinformatics, 03 medical and health sciences, Germline mutation, Dysmorphic feature, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Exome, Genetic Predisposition to Disease, Casein Kinase II, Child, Genetics (clinical), Exome sequencing, Germ-Line Mutation, Mutation, Pachygyria, High-Throughput Nucleotide Sequencing, medicine.disease, Body Dysmorphic Disorders, Hypotonia, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Female, medicine.symptom
Abstract

Whole exome sequencing (WES) can be used to efficiently identify de novo genetic variants associated with genetically heterogeneous conditions including intellectual disabilities. We have performed WES for 4102 (1847 female; 2255 male) intellectual disability/developmental delay cases and we report five patients with a neurodevelopmental disorder associated with developmental delay, intellectual disability, behavioral problems, hypotonia, speech problems, microcephaly, pachygyria and dysmorphic features in whom we have identified de novo missense and canonical splice site mutations in CSNK2A1, the gene encoding CK2α, the catalytic subunit of protein kinase CK2, a ubiquitous serine/threonine kinase composed of two regulatory (β) and two catalytic (α and/or α') subunits. Somatic mutations in CSNK2A1 have been implicated in various cancers; however, this is the first study to describe a human condition associated with germline mutations in any of the CK2 subunits.

Published
2016

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