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Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability
The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955779/ https://www.ncbi.nlm.nih.gov/pubmed/35328505 http://dx.doi.org/10.3390/ijms23063084 |
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author | Poeta, Loredana Malacarne, Michela Padula, Agnese Drongitis, Denise Verrillo, Lucia Lioi, Maria Brigida Chiariello, Andrea M. Bianco, Simona Nicodemi, Mario Piccione, Maria Salzano, Emanuela Coviello, Domenico Miano, Maria Giuseppina |
author_facet | Poeta, Loredana Malacarne, Michela Padula, Agnese Drongitis, Denise Verrillo, Lucia Lioi, Maria Brigida Chiariello, Andrea M. Bianco, Simona Nicodemi, Mario Piccione, Maria Salzano, Emanuela Coviello, Domenico Miano, Maria Giuseppina |
author_sort | Poeta, Loredana |
collection | PubMed |
description | The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants (CNVs) of the ARX locus found in patients presenting wide-ranging phenotypic variations including ID, speech delay, hypotonia and psychiatric abnormalities. We also report on a further novel Xp21.3 duplication detected in a male patient with moderate ID and carrying a fully duplicated copy of the ARX locus and the ultraconserved enhancers. As consequences of this rearrangement, the patient-derived lymphoblastoid cell line shows abnormal activity of the ARX-KDM5C-SYN1 regulatory axis. Moreover, the three-dimensional (3D) structure of the Arx locus, both in mouse embryonic stem cells and cortical neurons, provides new insight for the functional consequences of ARX duplications. Finally, by comparing the clinical features of the 16 CNVs affecting the ARX locus, we conclude that—depending on the involvement of tissue-specific enhancers—the ARX duplications are ID-associated risk CNVs with variable expressivity and penetrance. |
format | Online Article Text |
id | pubmed-8955779 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89557792022-03-26 Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability Poeta, Loredana Malacarne, Michela Padula, Agnese Drongitis, Denise Verrillo, Lucia Lioi, Maria Brigida Chiariello, Andrea M. Bianco, Simona Nicodemi, Mario Piccione, Maria Salzano, Emanuela Coviello, Domenico Miano, Maria Giuseppina Int J Mol Sci Review The X-linked gene encoding aristaless-related homeobox (ARX) is a bi-functional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders (NDDs); these include cortical malformations, paediatric epilepsy, intellectual disability (ID) and autism. In addition to point mutations, duplications of the ARX locus have been detected in male patients with ID. These rearrangements include telencephalon ultraconserved enhancers, whose structural alterations can interfere with the control of ARX expression in the developing brain. Here, we review the structural features of 15 gain copy-number variants (CNVs) of the ARX locus found in patients presenting wide-ranging phenotypic variations including ID, speech delay, hypotonia and psychiatric abnormalities. We also report on a further novel Xp21.3 duplication detected in a male patient with moderate ID and carrying a fully duplicated copy of the ARX locus and the ultraconserved enhancers. As consequences of this rearrangement, the patient-derived lymphoblastoid cell line shows abnormal activity of the ARX-KDM5C-SYN1 regulatory axis. Moreover, the three-dimensional (3D) structure of the Arx locus, both in mouse embryonic stem cells and cortical neurons, provides new insight for the functional consequences of ARX duplications. Finally, by comparing the clinical features of the 16 CNVs affecting the ARX locus, we conclude that—depending on the involvement of tissue-specific enhancers—the ARX duplications are ID-associated risk CNVs with variable expressivity and penetrance. MDPI 2022-03-13 /pmc/articles/PMC8955779/ /pubmed/35328505 http://dx.doi.org/10.3390/ijms23063084 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Poeta, Loredana Malacarne, Michela Padula, Agnese Drongitis, Denise Verrillo, Lucia Lioi, Maria Brigida Chiariello, Andrea M. Bianco, Simona Nicodemi, Mario Piccione, Maria Salzano, Emanuela Coviello, Domenico Miano, Maria Giuseppina Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title | Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title_full | Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title_fullStr | Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title_full_unstemmed | Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title_short | Further Delineation of Duplications of ARX Locus Detected in Male Patients with Varying Degrees of Intellectual Disability |
title_sort | further delineation of duplications of arx locus detected in male patients with varying degrees of intellectual disability |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955779/ https://www.ncbi.nlm.nih.gov/pubmed/35328505 http://dx.doi.org/10.3390/ijms23063084 |
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