Bourinaris, T;
Athanasiou, A;
Efthymiou, S;
Wiethoff, S;
Salpietro, V;
Houlden, H;
(2021)
Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders.
European Journal of Human Genetics
10.1038/s41431-021-00866-1.
(In press).
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Abstract
Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.
| Type: | Article |
|---|---|
| Title: | Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders. |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41431-021-00866-1 |
| Publisher version: | https://doi.org/10.1038/s41431-021-00866 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Genetics research, Movement disorders |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10125864 |
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