Angelman syndrome is a rare neurogenetic disorder characterized by microcephaly, seizures, ataxia, muscular hypotonia with hyperreflexia, and motor delay
Angelman syndrome is caused by deficiency of ubiquitin–protein ligase 3A gene (UBE3A) in the CNS
UBE3A deficiency impairs synapse formation and experience-dependent synapse remodelling
In neurons, the paternal UBE3A allele is silenced by a paternally expressed antisense transcript, so that only the maternal UBE3A allele is expressed
Novel therapeutic approaches are aimed at activating the silent paternal UBE3A allele
Translational research in rare diseases such as Angelman syndrome requires international collaborations between researchers, clinicians, caregivers, and parent and patient support groups
Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin–protein ligase E3A) gene on chromosome 15q11.2–q13. This loss of function can be caused by a mutation on the maternal allele, a 5–7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.
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We thank Jasmin Beygo and Deniz Kanber for critical reading of the manuscript. Part of this work was funded by the Bundesministerium für Bildung und Forschung (BMBF; Imprinting diseases, grant No. 01GM1513A).
The authors declare no competing financial interests.
- Uniparental disomy
A situation in which both copies of a chromosome are inherited from the same parent, rather than one being inherited from the mother and the other from the father.
- Genomic imprinting
An epigenetic process that leads to monoallelic gene expression in a parent-of-origin-specific manner. At imprinted loci, one parental gene copy is expressed while the other is silenced, leading to the existence of genes that are expressed from the paternal or maternal allele only.
- Non-homologous recombination
A recombination event that occurs between two chromosome regions with high but not identical DNA sequence similarity. Fusions among identical chromosome regions are termed homologous recombinations.
- Breakpoint cluster regions
Locations in the human genome where recurrent disruptions or breaks occur.
- Low copy repeats
Highly similar sequence elements within the human genome. They are typically 50–500 kb in length with >95% sequence identity. Low copy repeats are associated with regions of non-homologous recombination.
- Maternal nondisjunction
An event that occurs when chromosome pairs fail to separate during the first meiotic division, or when the two chromatids of a chromosome fail to separate during the second meiotic division, or during mitosis. Nondisjunction results in cells with abnormal chromosome numbers.
- Robertsonian translocation
Robertsonian translocations are chromosomal rearrangements that result from the fusion of the entire long arms of two acrocentric chromosomes. The five human acrocentric chromosome pairs are chromosomes 13, 14, 15, 21 and 22.
- Marker chromosome
A structurally abnormal chromosome fragment that cannot be unambiguously identified by conventional cytogenetics. The risk of phenotypic abnormalities associated with a marker chromosome depends on what genetic material is contained within the marker.
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Buiting, K., Williams, C. & Horsthemke, B. Angelman syndrome — insights into a rare neurogenetic disorder. Nat Rev Neurol 12, 584–593 (2016). https://doi.org/10.1038/nrneurol.2016.133
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