Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Jul;12(3):641-50.
doi: 10.1007/s13311-015-0361-y.

Angelman Syndrome

Seth S Margolis  1 , Gabrielle L Sell, Mark A Zbinden, Lynne M Bird
Affiliations
Review

Angelman Syndrome

Seth S Margolis et al. Neurotherapeutics. 2015 Jul.

Abstract

In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2% of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Organization of Chr15q11-q13 and schematic of UBE3A clinical mutations. (A) Diagram of maternal (MAT; top) and paternal (PAT; bottom) regions of human chromosome 15q11-q13. Green boxes represent actively expressed genes, while those whose expression have been silenced through genomic imprinting (maternal allele) or through expression of the antisense transcript [paternal ubiquitin protein ligase E3A (UBE3A)] are represented by red boxes. Active and inactive imprinting centers (IC) are represented by gray and white filled circles, respectively. Black triangles represent low copy number repeats that mediate deletions in the region. (B) Schematic of human UBE3A isoform 1 mapped with clinical mutations found in patients with Angelman syndrome. Exons (boxes) and intronic sequences (lines) are approximately to scale. The last 350 residues of UBE3A constitute its functional domain, the HECT (homologous to the E6-AP carboxyl terminus) ubiquitin ligase domain
Fig. 2
Fig. 2
Angelman syndrome (AS) diagnostic algorithm. FISH = fluorescent in situ hybridization
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140:413–418. doi: 10.1002/ajmg.a.31074. - DOI - PubMed
    1. Bird LM. Angelman syndrome: review of clinical and molecular aspects. Appl Clin Genet. 2014;7:93–104. doi: 10.2147/TACG.S57386. - DOI - PMC - PubMed
    1. Dagli A, Buiting K, Williams CA. Molecular and clinical aspects of Angelman syndrome. Mol Syndromol. 2012;2:100–112. - PMC - PubMed
    1. Williams CA, Driscoll DJ, Dagli AI. Clinical and genetic aspects of Angelman syndrome. Genet Med. 2010;12:385–395. doi: 10.1097/GIM.0b013e3181def138. - DOI - PubMed
    1. Williams CA. Looks like Angelman syndrome but isn’t—What is in the differential? RCPU Newsl 2011;22.

MeSH terms

Substances