Recessive NUP54 Variants Underlie Early‐Onset Dystonia with Striatal Lesions

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 NUP62related 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.

TorsinA is essential for the timing and localization of neuronal nuclear pore complex biogenesis

“…Neurons are heavily dependent on NPC function; neuronal plasticity requires transport of signaling molecules and transcription factors [3][4][5][6] and mRNA export for local translation is essential for several neurodevelopmental processes [7][8][9][10][11] . Accordingly, NPC defects are present in several nervous system diseases [12][13][14][15][16] and mutations in nucleoporins cause earlyonset neurological illness 17,18 . Indeed, neurons face a considerable challenge in maintaining proper nuclear function throughout their lifetime.…”

Nuclear pore dysfunction and disease: a complex opportunity

“…In the central channel, Nup54 mutations have been linked to infantile striatonigral degeneration, a disease that results in dystonia, ataxia, spasms, and difficulty swallowing [ 256 ]. Interestingly, disease-related Nup54 mutations are clustered in the C-terminus of the protein, which interacts with Nup62 [ 256 ].…”

“…In the central channel, Nup54 mutations have been linked to infantile striatonigral degeneration, a disease that results in dystonia, ataxia, spasms, and difficulty swallowing [ 256 ]. Interestingly, disease-related Nup54 mutations are clustered in the C-terminus of the protein, which interacts with Nup62 [ 256 ]. Separate work had previously identified Nup62 mutations which lead to bilateral striatal necrosis, a neurodegenerative disorder that affects the caudate nucleus and putamen of the basal ganglia [ 257 ].…”

“…Separate work had previously identified Nup62 mutations which lead to bilateral striatal necrosis, a neurodegenerative disorder that affects the caudate nucleus and putamen of the basal ganglia [ 257 ]. The phenotypes of patients with Nup54 and Nup62 mutations are remarkably similar [ 256 ], suggesting that proper interaction between central channel Nups is critical for neurological and motor functioning.…”

Coordinating nucleoporin condensation and nuclear pore complex assembly

“…Recently, loss of NPC integrity and nucleocytoplasmic shuttling have emerged as processes that are disturbed in in several aging-related neurodegenerative diseases, including Alzheimer's disease and ALS [124]. Mutations in Nups themselves can lead to diseases, including Dystonia [125,126], and nucleocytoplasmic transport can become disturbed by mutations in aggregation-prone proteins that sequester importins, Nups, or components of the Ran gradient needed for efficient transport [122][123][124][127][128][129][130]. These findings highlight the need for protein quality control at the nuclear envelope to ensure maintenance of the NPC and its efficient transport capabilities [131].…”