Angelman syndrome: review of clinical and molecular aspects

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Abstract

“Angelman syndrome” (AS) is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A ( UBE3A) gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling.

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UBE3A/E6-AP mutations cause Angelman syndrome.

T Kishino, M. Lalande, J Wagstaff (1997)

Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11-q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2-3% are caused by "imprinting mutations'. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5' end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3' splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.

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Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.

Y H Jiang, D. Armstrong, U Albrecht … (1998)

The E6-AP ubiquitin ligase (human/mouse gene UBE3A/Ube3a) promotes the degradation of p53 in association with papilloma E6 protein, and maternal deficiency causes human Angelman syndrome (AS). Ube3a is imprinted with silencing of the paternal allele in hippocampus and cerebellum in mice. We found that the phenotype of mice with maternal deficiency (m-/p+) for Ube3a resembles human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. Long-term potentiation (LTP) was severely impaired in m-/p+ mice despite normal baseline synaptic transmission and neuroanatomy, indicating that ubiquitination may play a role in mammalian LTP and that LTP may be abnormal in AS. The cytoplasmic abundance of p53 was increased in postmitotic neurons in m-/p+ mice and in AS, providing a potential biochemical basis for the phenotype through failure to ubiquitinate and degrade various effectors.

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De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.

T Matsuura, J Sutcliffe, P Fang … (1997)

Angelman syndrome (AS) is associated with maternal deletions of human chromosome 15q11-q13 and with paternal uniparental disomy for this region indicating that deficiency of an imprinted, maternally expressed gene within the critical interval is the likely cause of the syndrome. Although the gene for E6-AP ubiquitin-protein ligase (UBE3A) was mapped to the critical region for AS, evidence of expression from both parental alleles initially suggested that it was an unlikely candidate gene for this disorder. Because attempts to identify any novel maternally expressed transcripts were unsuccessful and because the UBE3A gene remained within a narrowed AS critical region, we searched for mutations in UBE3A in 11 AS patients without known molecular defects (large deletion, uniparental disomy, or imprinting mutation). This analysis tested the possibility that deficiency of an undefined, maternally expressed transcript or isoform of the UBE3A gene could cause AS. Four mutations were identified including a de novo frameshift mutation and a de novo nonsense mutation in exon 3 and two missense mutations of less certain significance. The de novo truncating mutations indicate that UBE3A is the AS gene and suggest the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript. Intragenic mutation of UBE3A in AS is the first example of a genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products.

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Author and article information

Journal

Journal ID (nlm-ta): Appl Clin Genet

Journal ID (iso-abbrev): Appl Clin Genet

Journal ID (publisher-id): The Application of Clinical Genetics

Title: The Application of Clinical Genetics

Publisher: Dove Medical Press

ISSN (Electronic): 1178-704X

Publication date Collection: 2014

Publication date (Electronic): 16 May 2014

Volume: 7

Pages: 93-104

Affiliations

[1 ]Department of Pediatrics, University of California, Division of Genetics, Rady Children’s Hospital, San Diego, California, USA

Author notes

Correspondence: Lynne M Bird, Rady Children’s Hospital, San Diego, Division of Dysmorphology/Genetics, 3020 Children’s Way #5031, San Diego, CA 92123, USA, Tel +1 858 966 5840, Fax +1 858 966 8550, Email lbird@ 123456rchsd.org

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Publisher ID: tacg-7-093

DOI: 10.2147/TACG.S57386

PMC ID: 4036146

PubMed ID: 24876791

SO-VID: ffff96f6-7e51-4d8e-a6a1-f6c8bd1781e3

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The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Angelman syndrome: review of clinical and molecular aspects

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Most cited references 137

UBE3A/E6-AP mutations cause Angelman syndrome.

Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.

De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.

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