Intellectual disability: dendritic anomalies and emerging genetic perspectives
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REVIEW
Intellectual disability: dendritic anomalies and emerging genetic perspectives Tam T. Quach1,2 · Harrison J. Stratton3 · Rajesh Khanna3 · Pappachan E. Kolattukudy4 · Jérome Honnorat2,5,6 · Kathrin Meyer7,8 · Anne‑Marie Duchemin9 Received: 11 August 2020 / Revised: 4 November 2020 / Accepted: 5 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention. Keywords Intellectual disability · Dendrite dysgenesis · Transgenic mice · CRMP3/DPYSL4 · Chromosome 10 (q26) deletion
5
French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France
6
SynatAc Team, Institut NeuroMyoGène, Lyon, France
7
INSERM U1217/CNRS, UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
The Research Institute of Nationwide Children Hospital, Columbus, OH 43205, USA
8
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA
Department of Pediatric,
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