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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome
Wiem Manoubi, Marwa Mahdouani, Dorra Hmida, Ameni Kdissa, Aida Rouissi, Ilhem Turki, Neji Gueddiche, Najla Soyah, Ali Saad, Christian Bouwkamp, Ype Elgersma, Soumaya Mougou-Zerelli, Moez Gribaa
Wiem Manoubi, Marwa Mahdouani, Dorra Hmida, Ameni Kdissa, Ali Saad, Soumaya Mougou-Zerelli, Moez Gribaa, Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Sousse 4000, Tunisia
Wiem Manoubi, Marwa Mahdouani, Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir 3000, Tunisia
Aida Rouissi, Ilhem Turki, Department of Neuropediatry, La Rabta Hospital, Tunis 2000, Tunisia
Neji Gueddiche, Department of Pediatric, Fattouma Bourguiba Hospital Monastir, Monastir 2003, Tunisia
Najla Soyah, Department of Pediatric, Farhat Hached University Hospital, Sousse 4000, Tunisia
Christian Bouwkamp, Ype Elgersma, Department of Neuroscience, Erasmus MC, the Netherlands, Rotterdam 3112 td, Netherlands
Author contributions: Manoubi W wrote the manuscript; Mahdouani M and Kdissa A revised the manuscript for scientific content; Hmida D, Rouissi A, Turki I, Gueddiche N, Soyah N and Mougou-Zerelli S diagnosed patients; Saad A, Bouwkamp C and Elgersma Y, designed the study and prepared of the manuscript; Gribaa M supervised and corrected the manuscript; All authors have read and approve the final manuscript.
Institutional review board statement: The study was reviewed and approved by the Science and Research Office of Farhat Hached Hospital.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that there is no conflict of interests.
Data sharing statement: All the parents of the suspected Angelman syndrome patients, whose samples and data were used in our research, have signed consent to share their samples and data with the physician/research responsible for the study. The consent is provided in French and Arabic which are the official languages of our country.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Wiem Manoubi, BSc, Research Scientist, Researcher, Laboratory of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat Hached University Hospital, Street Ibn El Jazzar, Sousse 4000, Tunisia.
wiem.manoubi@yahoo.fr
Received: October 31, 2023
Peer-review started: October 31, 2023
First decision: November 28, 2023
Revised: December 12, 2023
Accepted: January 4, 2024
Article in press: January 4, 2024
Published online: January 26, 2024
Processing time: 78 Days and 17.6 Hours
ARTICLE HIGHLIGHTS
Research background
The most important goal in our study is to investigate all the genes that may be responsible for the Angelman-like syndrome, since all the samples present the clinical features of Angelman syndrome (AS) without any genetic abnormalities responsible for the disease.
Research motivation
Exome sequencing of patients suspect to have AS, showed the presence of different genes that may be responsible for the disease clinicians that may have patients suspect to have AS, cannot look into ubiquitin-protein ligase E3A (UBE3A) gene but also to other genes already described and that may be responsible for AS.
Research objectives
The student of AS cohort patients is to our knowledge the first research study in the Tunisian patients, this study may help physicians to know how to diagnose the patients in case of the absence of all genetic alterations for AS and to look further for the Angelman-like syndromes. It help also to do functional studies that may be interesting for further treatment in the future.
Research methods
Patient with a strong suspicion of AS were assigned from pediatric departments and referred to Farhat Hached University Hospital. The chromosomal aberrations were assessed using constitutional investigations (karyotype, fluorescence in situ hybridization). The UBE3A gene was screened for mutation detection using Sanger method sequencing. The exome investigation was established using Illumina Hi-Seq 2000 sequencer. The exome data were analyzed using Genome Analysis Toolkit and Cartagenia software.
Research results
Sanger sequencing revealed several variants from which 3 novel ones not previously described. An interesting insertion involving exon 7 c.30-47_30-46 could be pathogenic and should be investigated further trough functional studies. The 22 potential genes displayed trough the exome sequencing brought to light new candidate genes to be investigated further for both AS and AS-Like syndromes.
Research conclusions
The physicians, geneticists and researchers have to investigate very carefully the suspected AS patients. in case of all the molecular and cytogenetics tests were negative for AS, they must go further with exome sequencing and think more about AS-like syndromes that may be responsible for the disease in the patients.
Research perspectives
However, additional evidence is required to clarify the developmental mechanism and timing of UBE3A repression in human neurons using cellular modeling by generating pluripotent stem cells (iPSCs) line derived from skin fibroblasts of AS patients. Subsequent research on iPSC holds the promise of advancing drug discovery, enhancing cell therapy, and introducing novel diagnostic approaches for neurogenetic disorders.
