Angelman syndrome is a genetic disorder that causes severe mental retardation, seizures, uncoordinated muscle movements, tremors, distinctive craniofacial features, and unique behavioral abnormalities. The disorder is caused by lack of function of one of the copies of a gene called UBE3A found on chromosome 15—specifically, deficiency of the copy of the gene that is inherited from the maternal side.

There are several human genes that are subject to "genomic imprinting," where one of the two inherited copies of a gene is silenced by chemical modification of the DNA (deoxyribonucleic acid) without alteration of the underlying nucleotide sequence. In the case of the UBE3A gene, the paternal copy is normally silenced, and expression of UBE3A from the maternal chromosome is therefore essential to prevent Angelman syndrome.

To date, there are four known types of genetic defect that can cause Angelman syndrome: (1) large deletions in the maternal copy of chromosome 15 that remove the UBE3A gene, (2) a situation called "paternal uniparental disomy," where both copies of chromosome 15 are inherited from the father and none from the mother, (3) defects in genomic imprinting that cause the maternal copy of the UBE3A gene to be silenced, and (4) small mutations in the maternal UBE3A gene that prevent the protein product from being created.

Ongoing research at the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center:

Further understanding of the disease
Several approaches are being taken at Baylor College of Medicine to understand genomic imprinting in general, and the mechanism of Angelman syndrome in particular. These experiments are being performed in cultured human cells and in mice.

At least two proteins have been identified that may be involved in the process of imprinting. Further experiments are investigating the functions of these proteins, and also the effect of generating mouse models without them.

A mouse gene called eed is also being studied because of its direct interaction with proteins that can modify DNA, and its involvement in brain development. Researchers are testing to determine whether eed is involved in the regulation of genomic imprinting.

Work towards therapy
Under normal circumstances, the maternally inherited copy of the UBE3A gene is active and the paternally inherited copy of the gene is silenced. However, in Angelman syndrome, the maternal UBE3A gene is deleted or nonfunctional and the paternal copy of the gene has only slight expression (not enough to prevent symptoms). One line of research at Baylor College of Medicine is a clinical trial using dietary supplements (folate and betaine) in an attempt to increase the leaky gene production from the paternal UBE3A gene. The goal is that this increased production would restore the enzyme activity that is lacking in Angelman syndrome, and thus reduce or eliminate clinical symptoms.

Baylor investigators working on Angelman syndrome:

Baylor MRDDRC projects associated with Angelman syndrome:

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Angelman syndrome resources:

Organizations: