The Ash Twins Blog

The human genome contains over 25000 genes encoding a dizzying number of proteins. These proteins together produce all of the biological processes necessary to give us life. The great majority of these genes are of unknown function, and finding a handhold to begin to grasp a gene’s role is surprisingly difficult, especially in the case of genes controlling nervous system development and operation. Spontaneous mutations in these genes provide just such a handhold.

It is a general property of DNA that it mutates in a somewhat random fashion. Any given person probably harbors about 175 new mutations in his/her genome, most or all of which are phenotypically insignificant. In some cases a mutation can alter or disrupt the function of a protein and cause a visible change in the individual’s anatomy or physiology. By identifying individuals which express common patterns of symptoms and screening their DNA, physician-scientists have been able to identify many genes which are involved in nervous system function. Dr. Harry Angelman’s recognition of his eponymous syndrome provides just such an example. Angelman reflected on his discovery of the Happy Puppet syndrome in a personal letter to his friend Dr. Charles Williams in 1991:

“The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman’s syndrome is one such story. It was purely by chance that nearly thirty years ago (e.g., circa 1964) three handicapped children were admitted at various times to my children’s ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona called . . . a Boy with a Puppet [Fig. 1]. The boy’s laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties.”

It was not until the 1990’s that Angelman Syndrome was convincingly linked to genetic abnormalities in a specific region of chromosome 15 (Nichols 1993), and it was not until 1997 that mutations in the gene encoding ubiquitin E3A ligase (UbE3A, also known as E6-associated protein, E6AP) were shown to be sufficient to cause the disorder (Kishino et al 1997). Since these seminal discoveries, our understanding of the cellular and molecular changes that lead to the symptoms of Angelman Syndrome has advanced considerably.

Angelman Syndrome’s distinct symptom profile, neurophysiology, epigenetics, molecular biology, and systems pathophysiology make it an especially fascinating disorder from the perspective of the neurobiology of disease. In the following several posts, I will review these aspects of the disorder.

Kishino T, Lalande M, Wagstaff J. (1997) “UBE3A/E6-AP mutations cause Angelman syndrome.” Nat Genet 15:70–73.

Nicholls, R.D. (1993) “Genomic imprinting and candidate genes in the Prader-Willi and Angelman syndromes.” Curr. Opin. Genet. Dev. 3: 445−456.