Genetic Mechanisms that Cause AS
In 1997, mutations in the gene, UBE3A located on chromosome 15, were identified as the cause of AS [1, 2]. All mechanisms known to cause AS either disrupt, inactivate or lead to absence of this gene on the maternally derived chromosome 15. There are several genetic “classes” or mechanisms that can disrupt UBE3A and thus cause AS [3, 4]. These mechanisms are depicted in this illustration.
A chromosome 15 pair is illustrated for each mechanism and a normal chromosome pair is depicted on the left with a normal q12 chromosome region. P = paternally-derived chromosome and M = maternal derivation. AS can be caused by a large deletion of the maternal chromosome 15q12 region (where the active UBE3A gene resides). AS can also be caused by inheritance from the father of 2 paternal chromosomes; a phenomenon termed paternal uniparental disomy (UPD). Another cause, referred to as an imprinting defect (ID), occurs when the chromosome 15 inherited from the mother has the paternal pattern of gene functioning so that UBE3A expression is actually turned off. The IC is located some distance from the UBE3A gene but it is still able to regulate UBE3A by a complex mechanism that is the subject of intense research. Finally, AS can be caused by a mutation in the UBE3A gene on the maternally derived chromosome 15.
|
Mechanism
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Frequency
(%)
|
|
Deletion
|
~70
|
|
UPD
|
2-3
|
|
Imprinting defect
|
3-5
|
|
UBE3A mutation or deletion
|
5-10
|
|
Other chromosome
Rearrangements
|
1-2
|
|
Unknown
|
10-15
|
The table indicates the prevalence of each genetic mechanism and also notes that about 10-15% of individuals with the clinical features of AS actually will have normal genetic studies. At this time, it is unclear if these individuals have the correct diagnosis or if they have other yet-to-be-identified genetic defects that cause AS.
The most common genetic mechanism causing AS is the large chromosome deletion. The diagram explains more information about this. The typical deletion region is indeed large and spans about 6 million molecules (base pairs) of DNA. Most deletions extend from break point one (BP1) to either BP2 or BP3 and are termed class I or class II deletions. About 10% of the deletions extend further beyond BP3, for example, at site BP4. New methods of clinical testing such as array-based comparative genomic hybridization can distinguish between class I and class II deletions. However, the FISH test will not be able to determine this. All the large deletions remove UBE3A from the maternally derived chromosome. The deletions also remove additional genes as pictured (e.g., GABA receptor genes) but UBE3A deletion causes essentially all the problems associated with AS.
1. Kishino T, Lalande MWagstaff J, UBE3A/E6-AP mutations cause Angelman syndrome [published erratum appears in Nat Genet 1997 Apr;15(4):411]. Nat Genet, 1997. 15(1): p. 70-3.
2. Matsuura T, Sutcliffe JS, Fang P, et al., De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet, 1997. 15(1): p. 74-7.
3. Jiang Y, Lev-Lehman E, Bressler J, et al., Genetics of Angelman syndrome. Am J Hum Genet, 1999. 65(1): p. 1-6.
4. Mann MR and Bartolomei MS, Towards a molecular understanding of Prader-Willi and Angelman Syndromes. Hum Mol Genet, 1999. 8(10): p. 1867-73.