Recessive NUP54 Variants Underlie Early-Onset Dystonia with Striatal Lesions

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Harrer, Philip | Schalk, Audrey | Shimura, Masaru | Baer, Sarah | Calmels, Nadege | Spitz, Marie Aude | Abi Warde, Marie-Thérèse | Schaefer, Elise | Kittke, Volker M. Sc | Dincer, Yasemin | Wagner, Matias | Dzinovic, Ivana | Berutti, Riccardo | Sato, Tatsuharu | Shirakawa, Toshihiko | Okazaki, Yasushi | Murayama, Kei | Oexle, Konrad | Prokisch, Holger | Mall, Volker | Melčák, Ivo | Winkelmann, Juliane | Zech, Michael

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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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