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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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