For several decades the chromosome study of angelman syndrome
individuals revealed no abnormalities, but with the development of
improved methods a very small deleted area was found in chromosome 15.
Molecular methods such as FISH (fluorescence in situ hybridization) now
demonstrate a deletion in about 70% of individuals with AS. The deleted
area, although extremely small, is actually quite large when viewed at
the molecular level. It is believed to be about 4 million base pairs in
length, enough to contain many genes.
The deleted region on chromosome 15 is known to contain genes that are
activated or inactivated depending upon the chromosome's parent of
origin (i.e., a gene may be turned on, on the chromosome 15 inherited
from the mother but off on the chromosome 15 inherited from the father).
This parent-specific gene activation is referred to as genetic
imprinting. Because the deletions seen in AS only occur on the
chromosome 15 inherited from the mother, the gene(s) responsible for AS
were predicted to be active only on the maternal chromosome 15.
Disruption of genes that are active on the paternally-derived chromosome
15 is now known to cause another developmental disorder termed the
Prader-Willi syndrome (PWS). The PWS gene(s) are actually located close
to the AS gene, but they are different.
In 1997, a gene within the AS deletion region called UBE3A was found to
be mutated in approximately 5% of AS individuals. These mutations can be
as small as 1 base pair. This gene encodes a protein called a ubiquitin
protein ligase, and UBE3A is believed to be the causative gene in AS.
All mechanisms known to cause AS appear to cause inactivation or absence
of this gene. UBE3A is an enzymatic component of a complex protein
degradation system termed the ubiquitin-proteasome pathway. This pathway
is located in the cytoplasm of all cells. The pathway involves a small
protein molecule, ubiquitin that can be attached to proteins thereby
causing them to be degraded. In the normal brain, the copy of UBE3A
inherited from the father is almost completely inactive, so the maternal
copy performs most of the UBE3A function in the brain. Inheritance of a
UBE3A mutation from the mother causes AS; inheritance of a UBE3A
mutation from the father has no detectable effect on the child. In some
families, AS caused by a UBE3A mutation can recur in more than one
family member.
Another cause of AS (2-3% of cases) is paternal uniparental disomy
(UPD), where the child inherits both copies of chromosome 15 from the
father, with no copy inherited from the mother. In this case, there is
no deletion or mutation, but the child is still missing the active UBE3A
gene because the paternal-derived chromosomes only have
brain-inactivated UBE3A genes.
A fourth class of AS individuals (3-5% of cases) have inherited
chromosome 15 copies from both mother and father, but the copy inherited
from the mother functions in the same way that a paternal chromosome 15
should function. This is referred to as an "imprinting defect". Some AS
individuals with imprinting defects have very small deletions of a
region called the Imprinting Center (IC). The IC regulates the activity
of UBE3A from a distant location, but how this regulation occurs is not
known. In some cases, AS caused by imprinting defects can recur in more
than one member of a family.
These discoveries have led to the realization that there are several
genetic "classes" or mechanisms that can cause AS. All of these
mechanisms lead to the typical clinical features of AS, although minor
differences may occur between and within groups.
Angelman Syndrome has confounded and confused the medical community and parents of Angelman individuals for hundreds of years. Initially presumed to be rare, it’s now believed thousands of Angelman Syndrome cases have gone undiagnosed or misdiagnosed as cerebral palsy, autism or other childhood disorders.
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About Us
- A Child Born with Angelman Syndrome
- I put this web blog up for my boy, he's my "Angel", my family and friends. To encourage parents, grandparents, legal guardians and care givers to advocate for their child, or the child they care for. To help enlighten the public about Angelman Syndrome. Possible links to finding and getting the necessary help. The challenges we go through, trying to get help for a child born with a genetic disability or any other disability. To enlighten school districts about Angelman Syndrome. These are very intelligent people who need extra help. Whether it be transportation needs, communication devices or on hands help. They are not to be hidden from society “shipped out of town” for their living or educational needs.
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