A Homozygous Missense Variant in PPP1R1B/DARPP‐32 Is Associated With Generalized Complex Dystonia

Autor: Anne Molitor, Gaoqun Zhang, Bruno Rinaldi, Sepand Rastegar, Muhammad Umair, Seiamak Bahram, Sylvie Friant, Mathieu Anheim, Sylvain Mayeur, Benoit Lhermitte, Stefan T. Arold, Amjad Khan, Béatrice Lannes, Raphael Carapito
Přispěvatelé: Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), GENOMAX [plateforme], Fédération Hospitalo-Universitaire OMICARE, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), CHU Strasbourg, Karlsruher Institut für Technologie (KIT), Génétique moléculaire, génomique, microbiologie (GMGM), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), King Saud Bin Abdulaziz University for Health Sciences [Riyadh] (KSAU-HS), Centurion University of Technology and Management [India], King Abdullah University of Science and Technology (KAUST), Centre de Biologie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), univOAK, Archive ouverte, Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Dopamine and cAMP-Regulated Phosphoprotein 32
autosomal recessive generalized dystonia
Movement disorders
Substantia nigra
Sciences du Vivant [q-bio]/Médecine humaine et pathologie
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
03 medical and health sciences
0302 clinical medicine
medicine
Missense mutation
Animals
Humans
Generalized epilepsy
Zebrafish
Exome sequencing
PPP1R1B
030304 developmental biology
Dystonia
Genetics
0303 health sciences
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
Homozygote
medicine.disease
biology.organism_classification
3. Good health
DARPP-32
Neurology
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Dystonic Disorders
Neurology (clinical)
medicine.symptom
exome sequencing
030217 neurology & neurosurgery
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: Movement Disorders
Movement Disorders, 2022, 37 (2), pp.365-374. ⟨10.1002/mds.28861⟩
Movement Disorders, Wiley, 2021, ⟨10.1002/mds.28861⟩
ISSN: 0885-3185
1531-8257
DOI: 10.1002/mds.28861⟩
Popis: Background: The dystonias are a heterogeneous group of hyperkinetic disorders characterized by sustained or intermittent muscle contractions that cause abnormal movements and/or postures. Although more than 200 causal genes are known, many cases of primary dystonia have no clear genetic cause.Objectives: To identify the causal gene in a consanguineous family with three siblings affected by a complex persistent generalized dystonia, generalized epilepsy, and mild intellectual disability.Methods: We performed exome sequencing in the parents and two affected siblings and characterized the expression of the identified gene by immunohistochemistry in control human and zebrafish brains.Results: We identified a novel missense variant (c.142G>A (NM_032192); p.Glu48Lys) in the protein phosphatase 1 regulatory inhibitor subunit 1B gene (PPP1R1B) that was homozygous in all three siblings and heterozygous in the parents. This gene is also known as dopamine and cAMP-regulated neuronal phosphoprotein 32 (DARPP-32) and has been involved in the pathophysiology of abnormal movements. The uncovered variant is absent in public databases and modifies the conserved glutamate 48 localized close to the serine 45 phosphorylation site. The PPP1R1B protein was shown to be expressed in cells and regions involved in movement control, including projection neurons of the caudate-putamen, substantia nigra neuropil, and cerebellar Purkinje cells. The latter cells were also confirmed to be positive for PPP1R1B expression in the zebrafish brain.Conclusions: We report the association of a PPP1R1B/DARPP-32 variant with generalized dystonia in man. It might be relevant to include the sequencing of this new gene in the diagnosis of patients with otherwise unexplained movement disorders. © 2021 International Parkinson and Movement Disorder Society.
Databáze: OpenAIRE
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