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

World Journal of Clinical Cases 2024年第3期12卷 503-516页

作者： 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 Laboratory of Human Cytogenetics Molecular Genetics and Reproductive BiologyFarhat Hached University HospitalSousse 4000Tunisia Higher Institute of Biotechnology of Monastir University of MonastirMonastir 3000Tunisia Department of Neuropediatry La Rabta HospitalTunis 2000Tunisia Department of Pediatric Farhat Hached University HospitalSousse 4000Tunisia Department of Neuroscience Erasmus MCthe NetherlandsRotterdam 3112 tdNetherlands

BACKGROUND angelman syndrome(AS)is caused by maternal chromosomal deletions,imprinting defects,paternal uniparental disomy involving chromosome 15 and the ubiquitin-protein ligase UBE3A gene mutations.However the genetic basis remains unclear for several patients.AIM To investigate the involvement of UBE3A gene in AS and identifying new potential genes using exome sequencing.METHODS We established a cohort study in 50 patients referred to Farhat Hached University Hospital between 2006 and 2021,with a strong suspicion of AS and absence of chromosomal aberrations.The UBE3A gene was screened for mutation detection.Two unrelated patients issued from consanguineous families were subjected to exome analysis.RESULTS We describe seven UBE3A variants among them 3 none previously described including intronic variants c.2220+14T>C(intron14),c.2507+43T>A(Exon15)and insertion in Exon7:c.30-47_30-46.The exome sequencing revealed 22 potential genes that could be involved in AS-like syndromes that should be investigated further.CONCLUSION Screening for UBE3A mutations in AS patients has been proven to be useful to confirm the diagnosis.Our exome findings could rise to new potential alternative target genes for genetic counseling.

关键词： angelman syndrome Ubiquitin-protein ligase E3A Exome Consanguinity Polymorphism

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A novel missense mutation of the ubiquitin protein ligase E3A gene in a patient with angelman syndrome

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Chinese Medical Journal 2011年第1期124卷 84-88页

作者： BAI Jin-li QU Yu-jin ZOU Li-ping YANG Xin-ying LIU Li-jun SONG Fang Department of Medical Genetics Capital Institute of Pediatrics Beijingl00020 China Department of Pediatrics Chinese People's Liberation Army General Hospital Beijing 100852 China Department of Neurology Beijing Children's Hospital Capital Medical University Beijing 100045 China

Background angelman syndrome （AS） is a neurogenetic disorder caused by an expression defect of the maternally inherited copy of ubiquitin protein ligase E3A （UBE3A） gene from chromosome 15. Although the most common genetic defects include maternal deletions of chromosome 15q11-13, paternal uniparental disomy and imprinting defect, mutations in the UBE3A gene have been identified in approximately 10% of AS patients. Methods A Chinese girl of 28 months presented clinical manifestation of AS. Genetic diagnosis and molecular genetic defects were studied by methylation-specific PCR （MS-PCR） and linkage analysis by short tandem repeat （STR）. We further performed sequence analysis of all the coding exons and flanking sequences of the UBE3A gene. The novel mutation screening was also performed in 100 unrelated healthy individuals to exclude the possibility of identifying a polymorphism variation. Results The MS-PCR analysis of the patient showed biparental inheritance of chromosome 15 with a normal methylation pattern in the 15q11-q13 region. And STR analysis revealed that the patient also inherited biparental alleles for six microsatellites. A novel mutation, cDNA1199 C〉A （p.P400H）, in exon 9 of the maternal UBE3A gene, was identified in the patient. Meanwhile, the mutation was observed in the patient＇s mother who had a normal phenotype. Conclusions It is necessary to perform the UBE3A gene mutation analysis in non-deletion/non-UPD/non-ID patients with AS. The clinical picture of the patient is concordant with that observed in previously reported AS patients with UBE3A mutation.

关键词： angelman syndrome ubiquitin protein ligase E3A mutation

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Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

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Neural Regeneration Research 2025年第3期20卷 715-724页

作者： Xin Yang Yu-Wen Alvin Huang John Marshall Department of Molecular Biology Cell Biology and BiochemistryBrown UniversityProvidenceRIUSA Department of Neurology Warren Alpert Medical School of Brown UniversityProvidenceRIUSA Center for Translational Neuroscience Robert J.and Nancy D.Carney Institute for Brain Science and Brown Institute for Translational ScienceBrown UniversityProvidenceRIUSA

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

关键词： angelman syndrome autism brain-derived neurotrophic factor depression neurodegenerative disorder neurodevelopmental disorder postsynaptic density protein-95 synaptic plasticity TrkB

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