Recessive <scp><i>NUP54</i></scp> Variants Underlie Early‐Onset Dystonia with Striatal Lesions
Philip Harrer, Audrey Schalk, Masaru Shimura, Sarah Baer, Nadège Calmels, Marie Aude Spitz, Marie‐Thérèse Abi Wardé, Élise Schaefer, Volker 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
Abstract
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.