-
Something wrong with this record ?
ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures
E. Poggio, L. Barazzuol, A. Salmaso, C. Milani, A. Deligiannopoulou, ÁG. Cazorla, SS. Jang, N. Juliá-Palacios, B. Keren, R. Kopajtich, SA. Lynch, C. Mignot, C. Moorwood, C. Neuhofer, V. Nigro, A. Oostra, H. Prokisch, V. Saillour, N. Schuermans,...
Language English Country United States
Document type Journal Article
- MeSH
- Plasma Membrane Calcium-Transporting ATPases MeSH
- Behavioral Symptoms MeSH
- Cerebellar Ataxia * genetics MeSH
- Dystonia * genetics MeSH
- Phenotype MeSH
- Humans MeSH
- Intellectual Disability * genetics MeSH
- Mice MeSH
- Hearing Loss * MeSH
- Neurodevelopmental Disorders * genetics MeSH
- Calcium MeSH
- Seizures genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
PURPOSE: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. METHODS: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. RESULTS: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. CONCLUSION: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.
2nd Department of Neurology Faculty of Medicine Comenius University Bratislava Slovakia
Center for Medical Genetics Ghent Ghent University Hospital Ghent Belgium
Centro Studi per la Neurodegenerazione University of Padua Padua Italy
Department of Biology University of Padua Padua Italy
Department of Biomedical Sciences University of Padua Padua Italy
Department of Biomolecular Medicine Ghent University Hospital Ghent Belgium
Department of Clinical Genetics Temple Street Children's University Hospital Dublin Ireland
Department of Neurology Zvolen Hospital Zvolen Slovakia
Department of Precision Medicine University of Campania Luigi Vanvitelli Napoli Italy
European Reference Network for Hereditary Metabolic Diseases Madrid Spain
Institute for Advanced Study Technical University of Munich Garching Germany
Institute of Human Genetics School of Medicine Technical University of Munich Munich Germany
Institute of Neurogenomics Helmholtz Zentrum München Munich Germany
Laboratoire de biologie médicale multisites Seqoia FMG2025 Paris France
Munich Cluster for Systems Neurology SyNergy Munich Germany
Neuroscience Center University of Padua Padua Italy
Seoul National University College of Medicine Seoul South Korea
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc24000494
- 003
- CZ-PrNML
- 005
- 20240213093222.0
- 007
- ta
- 008
- 240109s2023 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.gim.2023.100971 $2 doi
- 035 __
- $a (PubMed)37675773
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Poggio, Elena $u Department of Biology, University of Padua, Padua, Italy
- 245 10
- $a ATP2B2 de novo variants as a cause of variable neurodevelopmental disorders that feature dystonia, ataxia, intellectual disability, behavioral symptoms, and seizures / $c E. Poggio, L. Barazzuol, A. Salmaso, C. Milani, A. Deligiannopoulou, ÁG. Cazorla, SS. Jang, N. Juliá-Palacios, B. Keren, R. Kopajtich, SA. Lynch, C. Mignot, C. Moorwood, C. Neuhofer, V. Nigro, A. Oostra, H. Prokisch, V. Saillour, N. Schuermans, A. Torella, P. Verloo, E. Yazbeck, M. Zollino, R. Jech, J. Winkelmann, J. Necpal, T. Calì, M. Brini, M. Zech
- 520 9_
- $a PURPOSE: ATP2B2 encodes the variant-constrained plasma-membrane calcium-transporting ATPase-2, expressed in sensory ear cells and specialized neurons. ATP2B2/Atp2b2 variants were previously linked to isolated hearing loss in patients and neurodevelopmental deficits with ataxia in mice. We aimed to establish the association between ATP2B2 and human neurological disorders. METHODS: Multinational case recruitment, scrutiny of trio-based genomics data, in silico analyses, and functional variant characterization were performed. RESULTS: We assembled 7 individuals harboring rare, predicted deleterious heterozygous ATP2B2 variants. The alleles comprised 5 missense substitutions that affected evolutionarily conserved sites and 2 frameshift variants in the penultimate exon. For 6 variants, a de novo status was confirmed. Unlike described patients with hearing loss, the individuals displayed a spectrum of neurological abnormalities, ranging from ataxia with dystonic features to complex neurodevelopmental manifestations with intellectual disability, autism, and seizures. Two cases with recurrent amino-acid variation showed distinctive overlap with cerebellar atrophy-associated ataxia and epilepsy. In cell-based studies, all variants caused significant alterations in cytosolic calcium handling with both loss- and gain-of-function effects. CONCLUSION: Presentations in our series recapitulate key phenotypic aspects of Atp2b2-mouse models and underline the importance of precise calcium regulation for neurodevelopment and cerebellar function. Our study documents a role for ATP2B2 variants in causing heterogeneous neurodevelopmental and movement-disorder syndromes.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a myši $7 D051379
- 650 _2
- $a behaviorální symptomy $7 D001526
- 650 _2
- $a vápník $7 D002118
- 650 12
- $a cerebelární ataxie $x genetika $7 D002524
- 650 12
- $a dystonie $x genetika $7 D004421
- 650 12
- $a nedoslýchavost $7 D034381
- 650 12
- $a mentální retardace $x genetika $7 D008607
- 650 12
- $a neurovývojové poruchy $x genetika $7 D065886
- 650 _2
- $a fenotyp $7 D010641
- 650 _2
- $a ATPasy přenášející vápník přes plazmatickou membránu $7 D053499
- 650 _2
- $a záchvaty $x genetika $7 D012640
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Barazzuol, Lucia $u Department of Biomedical Sciences, University of Padua, Padua, Italy
- 700 1_
- $a Salmaso, Andrea $u Department of Biology, University of Padua, Padua, Italy
- 700 1_
- $a Milani, Celeste $u Department of Biology, University of Padua, Padua, Italy
- 700 1_
- $a Deligiannopoulou, Adamantia $u Department of Biomedical Sciences, University of Padua, Padua, Italy
- 700 1_
- $a Cazorla, Ángeles García $u European Reference Network for Hereditary Metabolic Diseases (MetabERN), Madrid, Spain; Neurometabolic Unit and Synaptic Metabolism Laboratory, Neurology Department Sant Joan de Déu Hospital, IPR, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- 700 1_
- $a Jang, Se Song $u Seoul National University (SNU) College of Medicine, Seoul, South Korea
- 700 1_
- $a Juliá-Palacios, Natalia $u Neurology Department, Neurometabolic Unit, Institut de Recerca, CIBERER and MetabERN, Hospital Sant Joan de Déu, Barcelona, Spain
- 700 1_
- $a Keren, Boris $u APHP.Sorbonne Université, Department of Medical Genetics, Pitié-Salpêtrière University Hospital, and Centre de Référence Maladies Rares Déficiences Intellectuelles de Causes Rares, Paris, France
- 700 1_
- $a Kopajtich, Robert $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany
- 700 1_
- $a Lynch, Sally Ann $u Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland
- 700 1_
- $a Mignot, Cyril $u APHP.Sorbonne Université, Department of Medical Genetics, Pitié-Salpêtrière University Hospital, and Centre de Référence Maladies Rares Déficiences Intellectuelles de Causes Rares, Paris, France
- 700 1_
- $a Moorwood, Catherine $u Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom
- 700 1_
- $a Neuhofer, Christiane $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany
- 700 1_
- $a Nigro, Vincenzo $u Department of Precision Medicine, University of Campania, Luigi Vanvitelli, Napoli, Italy
- 700 1_
- $a Oostra, Anna $u Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
- 700 1_
- $a Prokisch, Holger $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany
- 700 1_
- $a Saillour, Virginie $u Laboratoire de biologie médicale multisites Seqoia - FMG2025, Paris, France
- 700 1_
- $a Schuermans, Nika $u Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium
- 700 1_
- $a Torella, Annalaura $u Department of Precision Medicine, University of Campania, Luigi Vanvitelli, Napoli, Italy
- 700 1_
- $a Verloo, Patrick $u Department of Pediatric Neurology, Center for Inherited Metabolic Disorders and metabERN, University Hospital Ghent, Ghent, Belgium
- 700 1_
- $a Yazbeck, Elise $u Pediatric Neurology Department, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Saclay, Bicêtre Hospital, Le Kremlin Bicêtre, France
- 700 1_
- $a Zollino, Marcella $u Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- 700 1_
- $a Jech, Robert $u Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
- 700 1_
- $a Winkelmann, Juliane $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
- 700 1_
- $a Necpal, Jan $u 2nd Department of Neurology, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Department of Neurology, Zvolen Hospital, Zvolen, Slovakia
- 700 1_
- $a Calì, Tito $u Department of Biomedical Sciences, University of Padua, Padua, Italy; Centro Studi per la Neurodegenerazione (CESNE), University of Padua, Padua, Italy; Neuroscience Center (PNC), University of Padua, Padua, Italy
- 700 1_
- $a Brini, Marisa $u Department of Biology, University of Padua, Padua, Italy; Centro Studi per la Neurodegenerazione (CESNE), University of Padua, Padua, Italy
- 700 1_
- $a Zech, Michael $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany; Institute for Advanced Study, Technical University of Munich, Garching, Germany. Electronic address: michael.zech@mri.tum.de
- 773 0_
- $w MED00186213 $t Genetics in medicine $x 1530-0366 $g Roč. 25, č. 12 (2023), s. 100971
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/37675773 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20240109 $b ABA008
- 991 __
- $a 20240213093219 $b ABA008
- 999 __
- $a ok $b bmc $g 2049261 $s 1210188
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2023 $b 25 $c 12 $d 100971 $e 20230904 $i 1530-0366 $m Genetics in medicine $n Genet Med $x MED00186213
- LZP __
- $a Pubmed-20240109
