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Open AccessReview

NR4A2 as a Novel Target Gene for Developmental and Epileptic Encephalopathy: A Systematic Review of Related Disorders and Therapeutic Strategies

by Alba Gabaldon-Albero, Sonia Mayo and Francisco Martinez

Int. J. Mol. Sci. 2024, 25(10), 5198; https://doi.org/10.3390/ijms25105198 - 10 May 2024

Cited by 4 | Viewed by 3587

Abstract

The NR4A2 gene encodes an orphan transcription factor of the steroid–thyroid hormone–retinoid receptor superfamily. This review focuses on the clinical findings associated with the pathogenic variants so far reported, including three unreported cases. Also, its role in neurodegenerative diseases, such as Parkinson’s or Alzheimer’s disease, is examined, as well as a brief exploration on recent proposals to develop novel therapies for these neurological diseases based on small molecules that could modulate NR4A2 transcriptional activity. The main characteristic shared by all patients is mild to severe developmental delay/intellectual disability. Moderate to severe disorder of the expressive and receptive language is present in at least 42%, while neuro-psychiatric issues were reported in 53% of patients. Movement disorders, including dystonia, chorea or ataxia, are described in 37% patients, although probably underestimated because of its frequent onset in late adolescence–young adulthood. Finally, epilepsy was surprisingly present in 42% of patients, being drug-resistant in three of them. The age at onset varied widely, from five months to twenty-six years, as did the classification of epilepsy, which ranged from focal epilepsy to infantile spasms or Lennox–Gastaut syndrome. Accordingly, we propose that NR4A2 should be considered as a first-tier target gene for the genetic diagnosis of developmental and epileptic encephalopathy. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs, 2nd Edition)

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11 pages, 3072 KiB

Open AccessReview

Dopamine Transporter Deficiency Syndrome (DTDS): Expanding the Clinical Phenotype and Precision Medicine Approaches

by Joanne Ng, Serena Barral, Simon N. Waddington and Manju A. Kurian

Cells 2023, 12(13), 1737; https://doi.org/10.3390/cells12131737 - 28 Jun 2023

Cited by 8 | Viewed by 3620

Abstract

Infantile parkinsonism-dystonia due to dopamine transporter deficiency syndrome (DTDS) is an ultrarare childhood movement disorder caused by biallelic loss-of-function mutations in the SLC6A3 gene. Advances in genomic analysis have revealed an evolving spectrum of SLC6A3-related neurological and neuropsychiatric disorders. Since the initial clinical and genetic characterisation of DTDS in 2009, there have been thirty-one published cases with a variety of protein-truncating variants (nonsense variants, splice-site changes, and deletions) and missense changes. Amino acid substitutions result in mutant proteins with impaired dopamine transporter function due to reduced transporter activity, impaired dopamine binding, reduced cell-surface expression, and aberrant posttranslational protein modification with impaired glycosylation. In this review, we provide an overview of the expanding clinical phenotype of DTDS and the precision therapies in development, including pharmacochaperones and gene therapy. Full article

(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)

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15 pages, 2468 KiB

Open AccessArticle

Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia

by Kimberley M. Reid, Dora Steel, Sanjana Nair, Sanjay Bhate, Lorenzo Biassoni, Sniya Sudhakar, Michelle Heys, Elizabeth Burke, Erik-Jan Kamsteeg, Genomics England Research Consortium, Biju Hameed, Michael Zech, Niccolo E. Mencacci, Katy Barwick, Maya Topf and Manju A. Kurian

Cells 2023, 12(7), 1046; https://doi.org/10.3390/cells12071046 - 30 Mar 2023

Cited by 7 | Viewed by 3568

Abstract

The human dopaminergic system is vital for a broad range of neurological processes, including the control of voluntary movement. Here we report a proband presenting with clinical features of dopamine deficiency: severe infantile parkinsonism-dystonia, characterised by frequent oculogyric crises, dysautonomia and global neurodevelopmental impairment. CSF neurotransmitter analysis was unexpectedly normal. Triome whole-genome sequencing revealed a homozygous variant (c.110C>A, (p.T37K)) in DRD1, encoding the most abundant dopamine receptor (D₁) in the central nervous system, most highly expressed in the striatum. This variant was absent from gnomAD, with a CADD score of 27.5. Using an in vitro heterologous expression system, we determined that DRD1-T37K results in loss of protein function. Structure-function modelling studies predicted reduced substrate binding, which was confirmed in vitro. Exposure of mutant protein to the selective D₁ agonist Chloro APB resulted in significantly reduced cyclic AMP levels. Numerous D₁ agonists failed to rescue the cellular defect, reflected clinically in the patient, who had no benefit from dopaminergic therapy. Our study identifies DRD1 as a new disease-associated gene, suggesting a crucial role for the D₁ receptor in motor control. Full article

(This article belongs to the Special Issue Cell Metabolism: Lessons for Common Disease from Rare Metabolic Defects)

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