Trends in Genetics
ReviewKey role for gene dosage and synaptic homeostasis in autism spectrum disorders
Section snippets
What is autism?
The diagnosis of autism is based on impairments in two major domains – reciprocal social communication, and repetitive, stereotyped and ritualistic verbal and non-verbal behaviors. The term ‘autism spectrum disorders’ (ASD) is used as a shorthand to refer to any patient that meets these diagnostic criteria. But beyond this unifying definition lies an extreme degree of clinical heterogeneity, ranging from profound to moderate impairments, but always with functional disability. Indeed, autism is
Genetic variations and the modes of inheritance of ASD
In the absence of classical Mendelian inheritance, ASD were first thought to be a polygenic trait involving many loci. Therefore, model-free linkage studies, such as affected sib-pair analyses, were performed to identify susceptibility genes. Although many genomic regions were detected, only a restricted number of loci were replicated in independent scans (e.g. 7q31 and 17q11). To homogenize the genetic and phenotypic data and to gain higher statistical power, collaborative efforts were
Abnormal gene dosage in ASD
In recent years enormous progress has been achieved in detecting rare and frequent structural variants of the human genome, such as deletions, duplications and inversions [11]. At least nine studies have searched for such genomic imbalances in patients with ASD 5, 12, 13, 14, 15, 16, 17, 18, 19. Differences in patient inclusion criteria, genotyping methodologies and algorithms to detect deletions and duplications make the comparison of these results difficult. Nevertheless, it seems that there
Abnormal level of synaptic proteins
Several lines of evidence indicate that mutations in genes regulating various aspects of synaptogenesis and neuronal circuit formation (Figure 2) are associated with an increased risk for ASD. Among these, several genes seem to regulate the level of proteins at the synapse. Two X-linked genes, MECP2 (methyl-CpG-binding protein type 2) and FMR1 (fragile X mental retardation 1), are involved in autism ‘secondary’ to Rett and fragile X syndromes, respectively. MECP2 (Figure 2b) is a protein that
Abnormal formation of neuronal circuits in ASD
The main category of genes associated with ASD is related to the development and function of neuronal circuits [39]. At the synaptic membranes, cell adhesion molecules, such as NLGNs and NRXNs (Figure 2) are major organizers of excitatory glutamatergic and inhibitory GABAergic synapses, and contribute to the activity-dependent formation of neuronal circuits in mice [40]. Mutations identified in patients with ASD were found to alter the ability of NLGNs to trigger synapse formation in cultured
Abnormal synaptic homeostasis in ASD
Different homeostatic mechanisms allow neurons to maintain an optimal level of activity despite global changes in the overall activity of the network 64, 65, 66. Recent evidence suggests that homeostasis plays a role in the adaptation of synaptic plasticity by changing levels of activity 35, 64, and might be also associated with downscaling of synaptic weights during sleep [65]. Activity plays an important role in the refinement of brain connections during development and the first years of
Concluding remarks and perspectives
It is only a matter of time before geneticists will be able to obtain whole genome sequences of ASD patients. Exploring epigenetic alterations should be also more feasible in the near future, thanks to the availability of brain tissue samples and stem cells from patients. Animal models based on genetic results are now under scrutiny in many laboratories, and the consequence of the mutations and their reversibility is being analyzed at all levels from cell to behavior. However, more than ever we
Databases used in this review
DECIPHER v4.3; https://decipher.sanger.ac.uk/application/
Autism Genetic Database; (AGD) http://wren.bcf.ku.edu/
Autism CNV Database; http://projects.tcag.ca/autism_500k/
AutDB; http://www.mindspec.org/autdb.html
BioGPS; http://biogps.gnf.org/#goto=welcome
UCSC Genome browser; http://genome.ucsc.edu
Acknowledgments
This work was supported by the Institut Pasteur, Université Denis Diderot Paris 7, the INSERM, the CNRS, the Fondation Orange, and the Fondation de France Fondation FondaMentale.
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