What is Angelman Syndrome?
 

Angelman Syndrome (AS), also known as Angelman syndrome, is a neurodevelopmental disorder caused by abnormalities in the maternal allele of the UBE3A gene located in the 15q11-13 chromosomal region. Its main characteristics include severe developmental delay, intellectual disability, a happy demeanor with frequent laughter, language impairment, ataxia, and seizures. The incidence of AS is approximately 1 in 20,000 to 1 in 12,000.

 

Pathogenesis
 

The core etiology of Angelman Syndrome is the loss of function of the maternally inherited UBE3A gene. The expression of the UBE3A gene is subject to genomic imprinting, resulting in differential expression across human tissues. In normal brain tissue, the maternal UBE3A allele is actively expressed, while the paternal UBE3A allele is silenced due to transcriptional interference from the adjacent SNRPN gene. Therefore, defects in the maternal UBE3A allele lead to AS. The primary defect mechanisms include:Maternal deletion of chromosome 15q11-13 (70%-80%);
 

1.  Mutation in the maternal UBE3A gene (10%-20%);

2.  Paternal uniparental disomy (UPD) (3%-5%), where both copies of chromosome 15 are inherited from the father, leading to a complete absence of the maternal chromosome;

3.  Imprinting defect (3%-5%), which disrupts the expression of the maternal UBE3A allele.

(Image placeholder: Genotype-Phenotype Correlations in Angelman Syndrome)

 

Specifically, the loss of E6-AP ubiquitin ligase activity, encoded by the UBE3A gene, is central to AS pathogenesis. The absence of E6-AP prevents the degradation of its substrate Ephexin 5, leading to overactivation of the RhoA signaling pathway, reduced dendritic spine density, and impaired synapse formation. Concurrently, E6-AP's inability to degrade PTPA, an activator of phosphatase PP2A, results in abnormally high PP2A activity, disrupting intracellular neuronal signaling and affecting dendritic spine morphology. Furthermore, E6-AP deficiency causes accumulation of the autophagy regulator HAP1, inducing excessive autophagy and further impairing synaptic homeostasis. At the transcriptional level, the failure of E6-AP to function as a co-activator for the estrogen receptor leads to decreased Cyp26b1 gene expression, retinoic acid metabolism disruption, and impaired learning and memory. Finally, abnormal Na/K-ATPase activity combined with downregulation of miR-708 contributes to dysregulated intracellular calcium signaling. These mechanisms collectively lead to widespread synaptic plasticity and cognitive function deficits.

(Image placeholder: UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology)

 

Gene Therapy
 

Recombinant Adeno-Associated Virus (rAAV-UBE3A) Therapy: Intracerebroventricular (ICV) or targeted brain region (e.g., hippocampus, cerebellum) injection of rAAV vectors carrying the human UBE3A gene can restore UBE3A protein expression in maternal UBE3A-deficient mouse models, significantly improving motor coordination, cognitive deficits, and seizure-like symptoms.
 

Antisense Oligonucleotide (ASO) Therapy: ASOs are designed to target and suppress the expression of UBE3A-AS (UBE3A antisense transcript), thereby reactivating the silenced paternal UBE3A allele. This therapy has successfully restored paternal UBE3A gene expression and improved some behavioral deficits in mouse models.
 

RNA Editing Tools: Research teams are exploring RNA editing systems, such as ADAR-mediated editing, to target UBE3A-ATS, aiming to degrade or modify this transcript and relieve the silencing of the paternal allele.

 

Mouse Models
 

UBE3Am–/p+ Mice: Model the maternal 15q11-q13 deletion, exhibiting motor deficits, cognitive impairments, seizure susceptibility, sleep disturbances, and anxiety-like behavior.
 

Conditional UBE3A Knockout Mice: Deletion of UBE3A from inhibitory or excitatory neurons, used to study the neural circuit mechanisms underlying AS symptoms.
 

UBE3AYFP Mice: Knock-in of a yellow fluorescent protein (YFP) at the UBE3A locus, enabling visualization of endogenous UBE3A expression.
 

UBE3ASTOP/p+ Mice: Insertion of a Cre-excisable transcriptional terminator (STOP cassette) into the maternal UBE3A allele, resulting in loss of maternal UBE3A function.
 

UBE3AT Mice: Carrying a nonsense point mutation in the maternal UBE3A gene, modeling the human AS pathological state caused by loss of UBE3A enzymatic activity. These mice display motor coordination deficits, learning and memory impairments, and synaptic dysfunction.

 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various AS mouse models according to client needs, such as UBE3Am–/p+ mice, conditional UBE3A knockout mice, UBE3AYFP mice, and UBE3AT mice. We welcome inquiries!

 

References:

[1] Ruan Hongmei, Jiang Li. Research progress on the pathogenesis and genotype-phenotype correlation of Angelman syndrome. Chinese Journal of Applied Clinical Pediatrics, 2021, 36(22): 1750-1753. DOI: 10.3760/cma.j.cn101070-20200716-01197.

[2] Yang L, Shu X, Mao S, Wang Y, Du X, Zou C. Genotype-Phenotype Correlations in Angelman Syndrome. Genes (Basel). 2021 Jun 28;12(7):987. doi: 10.3390/genes12070987. PMID: 34203304; PMCID: PMC8304328.

[3] Wolter, J.M., James, L.M., Boeshore, S.L. et al. AAV-dCas9 vector unsilences paternal UBE3A in neurons by impeding UBE3A-ATS transcription. Commun Biol 8, 1332 (2025).

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