Genetic investigation of the ubiquitin-protein ligase E3A gene as putative target in Angelman syndrome

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.