Recessive NUP54 Variants Underlie Early-Onset Dystonia with Striatal Lesions.
Philip Harrer, Audrey Schalk, Masaru Shimura, Sarah Baer, Nadège Calmels, Marie Aude Spitz, Marie-Thérèse Abi Warde, Elise Schaefer, Volker M Sc Kittke, Yasemin Dincer, Matias Wagner, Ivana Dzinovic, Riccardo Berutti, Tatsuharu Sato, Toshihiko Shirakawa, Yasushi Okazaki, Kei Murayama, Konrad Oexle, Holger Prokisch, Volker Mall, Ivo Melčák, Juliane Winkelmann, Michael Zech
Author Information
Philip Harrer: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Audrey Schalk: Institut de génétique médicale d'Alsace (IGMA), Laboratoires de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, France.
Masaru Shimura: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Sarah Baer: Department of Neuropediatrics, ERN EpiCare, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Nadège Calmels: Institut de génétique médicale d'Alsace (IGMA), Laboratoires de Diagnostic Génétique, Hôpitaux universitaires de Strasbourg, Strasbourg, France.
Marie Aude Spitz: Department of Neuropediatrics, ERN EpiCare, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Marie-Thérèse Abi Warde: Department of Neuropediatrics, ERN EpiCare, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Elise Schaefer: Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Volker M Sc Kittke: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Yasemin Dincer: Lehrstuhl für Sozialpädiatrie, Department of Pediatrics, Technische Universität München, Munich, Germany.
Matias Wagner: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. ORCID
Ivana Dzinovic: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Riccardo Berutti: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Tatsuharu Sato: Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.
Toshihiko Shirakawa: Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.
Yasushi Okazaki: Diagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan. ORCID
Kei Murayama: Center for Medical Genetics, Department of Metabolism, Chiba Children's Hospital, Chiba, Japan. ORCID
Konrad Oexle: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. ORCID
Holger Prokisch: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. ORCID
Volker Mall: Lehrstuhl für Sozialpädiatrie, Department of Pediatrics, Technische Universität München, Munich, Germany.
Ivo Melčák: Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia, USA.
Juliane Winkelmann: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Michael Zech: Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany. ORCID
Infantile striatonigral degeneration is caused by a homozygous variant of the nuclear-pore complex (NPC) gene NUP62, involved in nucleo-cytoplasmic trafficking. By querying sequencing-datasets of patients with dystonia and/or Leigh(-like) syndromes, we identified 3 unrelated individuals with biallelic variants in NUP54. All variants clustered in the C-terminal protein region that interacts with NUP62. Associated phenotypes were similar to those of NUP62-related disease, including early-onset dystonia with dysphagia, choreoathetosis, and T2-hyperintense lesions in striatum. In silico and protein-biochemical studies gave further evidence for the argument that the variants were pathogenic. We expand the spectrum of NPC component-associated dystonic conditions with localized basal-ganglia abnormalities. ANN NEUROL 2023;93:330-335.
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