Autism-World

In 1996/1997, the laboratories of Dr. Joseph Wagstaff from Children’s Hospital in Boston and Harvard School of Medicine and Dr. Arthur Beaudet from Baylor College of Medicine found a single gene on chromosome l5q called UBE3A that caused Angelman syndrome (figure 3). They showed that some patients with AS have mutations in the UBE3A gene. The gene encodes a protein called E6-AP ubiquitin protein ligase (also known as ubiquitin ligase 3). The exact mechanism of how the deficiency of this protein causes the clinical features of AS is not completely understood. However, it is known that E6-AP acts as an enzyme necessary for normal protein turnover within cells. This may suggest that the clinical findings are due to failure to degrade various proteins, accumulation of which may be deleterious to an individual.

What makes the UBE3A gene unique, is that it demonstrates tissue specific imprinting. The gene is expressed from maternal and paternal alleles in all tissues (organs) except specific parts of the central nervous system. UBE3A is imprinted in the human brain with the paternal copy of the gene being naturally silenced. In other words, in the brain the UBE3A is only expressed from the maternal copy. If this does not happen due to a mutation or deletion of UBE3A, the enzyme is not made and it is thought that certain proteins are not degraded in the brain. Recent animal studies have shown that the gene is preferentially expressed from the maternal allele with silencing of the paternal allele in the hippocampus and cerebellum in mice brains. The tissue specific imprinting tits the clinical presentation of AS since affected individuals have various neurologic problems and complications, but do not have involvement of other organ systems.

As mentioned above, UBE3A is naturally silenced on the paternally inherited copy in certain parts of the brain. Therefore, if a UBE3A mutation is inherited from the father, the person is unaffected as the paternal copy is not expressed. If the carrier of the UBE3A mutation is a male, he has a 50% chance of passing on the mutation, but is not at risk of having children with AS. Again, it is because the paternally inherited copy of the UBE3A gene is naturally silenced in the brain. if the carrier of the UBE3A mutation is a female, she also has a 50% chance of passing on the mutation. However, in this case if the mutation is passed on, the child will have Angelman syndrome. This is due to the fact that the maternal copy of the UBE3A gene has to function in the brain as the paternal copy is naturally silenced.

Technorati : Angelman Syndrome

This entry was posted on Monday, September 10th, 2007 at 4:41 pm and is filed under Angelman Syndrome.