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.

The mammalian telencephalon contains a tremendous diversity of GABAergic projection neuron and interneuron types, that originate in a germinal zone of the embryonic basal ganglia. How genetic information in this transient structure is transformed into different cell types is not yet fully understood. Using a combination ofin vivolineage tracing, CRISPR perturbation and ChIP-seq in mice, we found that the transcription factor MEIS2 favors the development of projection neurons through genomic binding sites in regulatory enhancers of projection neuron specific genes. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity towards these sites. In interneurons, the activation of projection neuron specific enhancers by MEIS2 and DLX5 is repressed by the transcription factor LHX6. When MEIS2 carries a mutation associated with intellectual disability in humans, it is less effective at activating enhancers involved in projection neuron development. This suggests that GABAergic differentiation may be impaired in patients carrying this mutation. Our research has uncovered a mechanism by which the selective activation of enhancers plays a crucial role in the establishment of neuronal identity, as well as in potential pathological mechanisms.

BackgroundProtein synthesis is a tightly controlled process, involving a host of translation‐initiation factors and microRNA‐associated repressors. Variants in the translational regulator EIF2AK2 were first linked to neurodevelopmental‐delay phenotypes, followed by their implication in dystonia. Recently, de novo variants in EIF4A2, encoding eukaryotic translation initiation factor 4A isoform 2 (eIF4A2), have been described in pediatric cases with developmental delay and intellectual disability.ObjectiveWe sought to characterize the role of EIF4A2 variants in dystonic conditions.MethodsWe undertook an unbiased search for likely deleterious variants in mutation‐constrained genes among 1100 families studied with dystonia. Independent cohorts were screened for EIF4A2 variants. Western blotting and immunocytochemical studies were performed in patient‐derived fibroblasts.ResultsWe report the discovery of a novel heterozygous EIF4A2 frameshift deletion (c.896_897del) in seven patients from two unrelated families. The disease was characterized by adolescence‐ to adulthood‐onset dystonia with tremor. In patient‐derived fibroblasts, eIF4A2 production amounted to only 50% of the normal quantity. Reduction of eIF4A2 was associated with abnormally increased levels of IMP1, a target of Ccr4‐Not, the complex that interacts with eIF4A2 to mediate microRNA‐dependent translational repression. By complementing the analyses with fibroblasts bearing EIF4A2 biallelic mutations, we established a correlation between IMP1 expression alterations and eIF4A2 functional dosage. Moreover, eIF4A2 and Ccr4‐Not displayed significantly diminished colocalization in dystonia patient cells. Review of international databases identified EIF4A2 deletion variants (c.470_472del, c.1144_1145del) in another two dystonia‐affected pedigrees.ConclusionsOur findings demonstrate that EIF4A2 haploinsufficiency underlies a previously unrecognized dominant dystonia‐tremor syndrome. The data imply that translational deregulation is more broadly linked to both early neurodevelopmental phenotypes and later‐onset dystonic conditions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.