http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11827743&dopt=Abstract
Molecular genetics and animal models in autistic disorder.
Andres C.
INSERM U316, Tours Cedex, France
Autistic disorder is a behavioural syndrome beginning before the age of 3 years
and lasting over the whole lifetime. It is characterised by impaired
communication, impaired social interactions, and repetitive interests and
behaviour. The prevalence is about 7/10,000 taking a restrictive definition and
more than 1/500 with a broader definition, including all the pervasive
developmental disorders. The importance of genetic factors has been highlighted
by epidemiological studies showing that autistic disorder is one of the most
genetic neuropsychiatric diseases. The relative risk of first relatives is about
100-fold higher than the risk in the normal population and the concordance in
monozygotic twin is about 60%. Different strategies have been applied on the
track of susceptibility genes. The systematic search of linked loci led to
contradictory results, in part due to the heterogeneity of the clinical
definitions, to the differences in the DNA markers, and to the different methods
of analysis used. An oversimplification of the inferred model is probably also
cause of our disappointment. More work is necessary to give a clearer picture.
One region emerges more frequently: the long arm of chromosome 7. Several
candidate genes have been studied and some gave indications of association: the
Reelin gene and the Wnt2 gene. Cytogenetical abnormalities are frequent at
15q11-13, the region of the Angelman and Prader-Willi syndrome. Imprinting plays
an important role in this region, no candidate gene has been identified in
autism. Biochemical abnormalities have been found in the serotonin system.
Association and linkage studies gave no consistent results with some serotonin
receptors and in the transporter, although it seems interesting to go further in
the biochemical characterisation of the serotonin transporter activity,
particularly in platelets, easily accessible. Two monogenic diseases have been
associated with autistic disorder: tuberous sclerosis and fragile X. A better
knowledge of the pathophysiology of these disorders can help to understand
autism. Different other candidate genes have been tested, positive results await
replications in other samples. Animal models have been developed, generally by
knocking out the different candidate genes. Behaviour studies have mainly
focused on anxiety and learning paradigms. Another group of models results from
surgical or toxic lesions of candidate regions in the brain, in general during
development. The tools to analyse these animals are not yet standardised, and an
important effort needs to be undertaken.
PMID: 11827743 [PubMed - in process]
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