The spectrum of mutations in UBE3A causing Angelman syndrome
Open accessAbstract
Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.
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Features of Angelman, Phelan McDermid, and Smith-Magenis syndromes can be recapitulated by point mutations in UBE3A, SHANK3, and RAI1 respectively.
“For example, clinical features of Angelman, Phelan McDermid and Smith-Magenis Syndromes, which are caused by large deletions of multiple genes, can be recapitulated by point mutations in UBE3A (Fang et al., 1999) and SHANK3 (Bonaglia et al., 2006) and RAI1 (Slager et al., 2003) respectively.”
From Getting to the cores of autism (2019) · cites this paper as Fang et al., 1999
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“For example, clinical features of Angelman, Phelan-McDermid, and Smith-Magenis syndromes, which are caused by large deletions of multiple genes, can be recapitulated by point mutations in UBE3A (Fang et al., 1999), SHANK3 (Bonaglia et al., 2006), and RAI1 (Slager et al., 2003), respectively.”
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- Authors
- Fang, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Fang, P
- ORCID
- Fang, P
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-01-01
- Volume
- 8
- Issue
- 1
- Pages
- 129-135
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2112272513
- Cited by
- 159
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 2 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 9
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- National Institutes of Health (RR-00188)
- National Center for Research Resources (RR 00188)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, P30HD024064)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Angelman syndrome, UBE3A, loss-of-function mutations, imprinting, paternal uniparental disomy, chromosome 15q11-q13, truncating mutations, de novo mutations, genotype-phenotype correlation, genetic counseling, DNA methylation
- MeSH terms
- Animals, Base Sequence, DNA Mutational Analysis, Exons, Female, Genetic Counseling, Humans, Ligases, Male, Mutation, Pedigree, Phenotype, Genetic Variation, Angelman Syndrome, DNA Primers, Genomic Imprinting, Ubiquitin-Protein Ligases, Mice
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