Researchers have proposed a new hypothesis on the cause of autism,
suggesting a mixed epigenetic and genetic and mixed de novo and
inherited (MEGDI) model. Their hypothesis, and evidence to support it,
will be published September 8, 2004 in the online edition of the
American Journal of Medical Genetics Part A, and will be available via
Wiley InterScience at http://www.interscience.wiley.com/journal/ajmg.
The role of genetics in autism is believed to be significant because
twin studies have found that identical twins, who have the same DNA, are
much more likely to share the diagnosis than fraternal twins. However,
experts have not yet identified the specific genetic components related
to autism, and many experts believe that multiple genes are involved.
Researchers, led by Yong-hui Jiang of Baylor College of Medicine in
Houston, propose that most cases of autism can be explained by a complex
model for genetic malfunction that may or may not include an altered DNA
sequence. Where the DNA sequence is intact, the researchers believe that
gene expression could be faulty. They suggest that some of these genetic
factors are inherited, and others occur de novo in genes of the autistic
person. In this study, they formulate a five-part hypothesis on the
cause of autism:
Based on the evidence of parent-of-origin effects, they propose that
there is a major epigenetic (related to gene expression, not sequence)
component in the etiology of autism involving genetic imprinting.
They suggest that epigenetic and genetic factors (both de novo and
inherited) cause autism through dysregulation of two or more principal
genes, one of which maps within chromosomes 15q11-q13, with the Angelman
gene encoding E6-AP ubiquitin-protein ligase (UBE3A) being the strongest
candidate in this region
They propose that the dysregulation of UBE3A involves some combination
of overexpression, gene silencing, or misexpression of the three
potential isoforms of E6-AP
They believe twin data on autism are best explained by de novo defects
(epigenetic or genetic) arising in germ cells or in the embryo prior to
twinning
They speculate that one or more additional genes whose function affects
the role of UBE3A likely participate with the Angelman gene in an
oligogenic inheritance model.
The researchers reviewed available evidence and conducted their own
investigations to test elements of their hypothesis. For example, from
evidence that maternal, but not paternal, inheritance of extra material
from chromosome 15 causes autism in a small fraction of cases, they
suggest that this chromosome, and more specifically, the gene for
Angelman syndrome in this region, plays a greater role in autism than is
currently appreciated. They also noted the difference in the effects of
a gene depending on which parent transmits it, which strongly suggests
an epigenetic effect called genomic imprinting.
The authors do not argue that their data prove the components of the
oligogenic hypothesis. They say, rather, that the model is generally
compatible with the data presented, it represents some fresh
perspectives for autism, and it can be tested in a number of ways.
"We believe that this model is highly likely to apply to some small
fraction of autism cases," say the authors, "but more importantly and
more speculatively, we propose that it will explain the majority of
cases of autism."
The oligogenic model does not entirely rule an environmental role in
autism. "The epigenetic component of the oligogenic model can be
considered in the context of possible environmental factors affecting
the risk of de novo imprinting defects. Non-genetic factors could affect
the risk for an epigenetic form of autism," the authors conclude.
If the MEGDI model is correct for autism, it could also be relevant to
other disorders, such as schizophrenia or bipolar mood disorder that
clearly have a genetic component but have resisted understanding despite
the completion of the human genome project.
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Article: "A Mixed Epigenetic/Genetic Model for Oligogenic Inheritance of
Autism With a Limited Role for UBE3A." Yong-hui Jiang, Trilochan Sahoo,
Ron C. Michaelis, Dani Bercovich, Jan Bressler, Catherine D. Kashork,
Qian Liu, Lisa G. Shaffer, Richard J. Schroer, David W. Stockton,
Richard S. Spielman, Roger E. Stevenson, and Arthur L. Beaudet; American
Journal of Medical Genetics Part A; Published Online: September 8, 2004
(DOI: 10.1002/ajmg.a.30297).