UBE3A – Angelman Syndrome

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by profound intellectual disability, speech impairment, ataxia, seizures, and a distinctive happy demeanor. Pathogenic variants in the maternally expressed ubiquitin-protein ligase gene UBE3A (HGNC:12496) underlie ~10–15% of AS cases, with the majority resulting from large maternal deletions, paternal uniparental disomy, imprinting defects, or intragenic mutations affecting the maternal allele.

1. Clinical Validity

Combined data from over 200 unrelated individuals with AS and UBE3A variants (e.g., 56 clinically ascertained NDUI patients with UBE3A mutations (PMID:9887341); >100 deletion or UPD cases) and extensive segregation in familial cases establish a Definitive gene–disease relationship. ClinGen Category: Definitive

2. Genetic Evidence

AS due to UBE3A follows an autosomal dominant imprinting model with maternal allele expression. Segregation in multiple families has identified ≥8 affected relatives with maternally inherited UBE3A variants. Case series report >200 affected probands harboring UBE3A variants, including missense, frameshift, nonsense, and splice-site changes. Recurrent variants include c.1504C>T (p.Arg502Ter) in exon 9 (PMID:9585605).

3. Functional Evidence

Mouse models with maternal Ube3a deficiency recapitulate AS neurological and EEG phenotypes, demonstrating impaired motor learning and seizures (PMID:11895368). Biochemical assays of patient-derived point mutants show loss of E3 ubiquitin ligase activity and proteasome dysfunction (PMID:15263005).

4. Conflicting Evidence

Reports that Ube3a expression is unaltered in Mecp2 mutant mice (PMID:16754645) reflect mechanistic studies rather than challenge UBE3A’s role in AS.

5. Integration and Conclusion

Genetic and functional studies coherently link loss of maternal UBE3A function to the AS phenotype, with a range of variant classes causing E3 ligase deficiency, disrupted proteasomal interactions, and altered synaptic signaling. While additional substrates and modifier loci continue to be investigated, the clinical utility of UBE3A testing for AS diagnosis and genetic counseling is well established.

Key Take-home: Maternal UBE3A loss-of-function is the definitive cause of Angelman syndrome, supporting its use in molecular diagnosis and guiding recurrence risk assessment.

References

• Nature genetics • 1997 • UBE3A/E6-AP mutations cause Angelman syndrome. PMID:8988171
• Human molecular genetics • 1999 • The spectrum of mutations in UBE3A causing Angelman syndrome. PMID:9887341
• Neurobiology of disease • 2002 • Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. PMID:11895368
• The Journal of biological chemistry • 2004 • Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein. PMID:15263005

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