[Homestead] Genetics of Autism, Asperger's

Tvoivozhd tvoivozd at infionline.net
Thu Sep 9 14:39:12 EDT 2004

/Source:/ 	*John Wiley & Sons, Inc.* 	
/Date:/ 	2004-09-08
/URL:/ 	http://www.sciencedaily.com/releases/2004/09/040908082507.htm


    New Genetic Hypothesis For The Cause Of Autism

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 

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.


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).


/This story has been adapted from a news release issued by John Wiley & 
Sons, Inc../

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