Till startsida
University of Gothenburg
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"The Human Genetics and Cognitive Functions Unit", Institut Pasteur, Paris, France

Background: Autism spectrum disorders (ASD) are a heterogeneous group of pervasive neurodevelopmental disorders affecting 1% of the population. The diagnosis of ASD is based on impairments in reciprocal social communication and stereotyped behaviors. In addition to these core features, ASD are sometimes associated with endophenotypes such as macrocephaly and abnormal serotonin/melatonin blood levels. Although ASD are considered as the most genetic of the psychiatric disorders, their causes remain largely unknown.

Past achievements: The Human Genetics and Cognitive Function group is headed by Thomas Bourgeron and gathers psychiatrists, neuroscientists and geneticists to understand the causes of ASD. In collaboration with Marion Leboyer in France and Christopher Gillberg in Sweden, they identified the first synaptic pathway associated with ASD – the NLGN-NRXN-SHANK pathway (Jamain et al. Nature Genetics 2003; Durand et al. Nature Genetics 2007, Szatmari et al., Nature Genetics, Pinto et al. Nature 2012). This pathway is known for playing a role in synapse formation and in the excitatory-inhibitory balance within the brain. Their results have highlighted the genetic heterogeneity of ASD, but also identified the first common synaptic pathway for this disorder. In addition, animal models were generated to better characterise the mechanisms leading to autism (e.g. Nlgn4 KO in Jamain et al. PNAS 2008). To date, the NLGN-NRXN-SHANK pathway constitutes one of the most relevant targets to identify new treatments for ASD. In parallel, the first mutations within the melatonin pathway, which could modulate synaptic currents and contribute to the major sleep problems observed in patients with ASD, were identified (Melke et al. Molecular Psychiatry 2008).

Current projects: The current projects include a thorough genomic and clinical profiling of 300-500 patients with ASD using high-throughput genotyping/sequencing and brain imaging. In parallel, we are focusing on a set of mutations that we identified within NLGN and SHANK genes by studying in depth their functional impacts at the clinical, neuronal and mouse behavior levels. In line with this, we recently described the presence of multiple genetic hits in patients with ASD carrying a SHANK2 de novo deletion (Leblond et al. PLoS Genetics 2012) as well as the hyperactivity and the autistic like phenotype of mice lacking SHANK2 (Schmeisser et al. Nature 2012). The Paris lab is now engaged in a special effort to reverse the observed deficits using human induced pluripotent stem cells (iPSC) and mouse models carrying synaptic gene mutations. Our group also develops new methods for analysing whole genome and brain imaging data as well as new paradigms for characterising mouse social and vocal behavior. Overall, the aim of our laboratory is to offer an evidence-based approach to ASD that should help improve diagnosis, care and integration of services for the patients.


Anney, R., Klei, L., Pinto, D., Almeida, J., Bacchelli, E., Baird, G., … Devlin, B. (2012). Individual common variants exert weak effects on the risk for autism spectrum disorders. Human Molecular Genetics, 21, 4781-4792.

Botros, H.G., Legrand, P., Pagan, C., Bondet, V., Weber, P., Ben-Abdallah, M., … Bourgeron, T. (2012). Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. Journal of Pineal Research, (Epub ahead of print).

Chaste, P., Betancur, C., Gérard-Blanluet, M., Bargiacchi, A., Kuzbari, S., Drunat, S., … Delorme, R. (2012). High-functioning autism spectrum disorder and fragile X syndrome: report of two affected sisters. Molecular Autism, 3, 5.

El-Kordi, A., Winkler, D., Hammerschmidt, K., Kästner, A., Krueger, D., Ronnenberg, A., … Ehrenreich, H. (2012). Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism. Behavioural Brain Research, (Epub ahead of print).

Etain, B., Dumaine, A., Bellivier, F., Pagan, C., Francelle, L., Goubran-Botros, H., … Jamain, S. (2012). Genetic and functional abnormalities of the melatonin biosynthesis pathway in patients with bipolar disorder. Human Molecular Genetics, 21, 4030-4037.

Ey, E., Yang, M., Katz, A.M., Woldeyohannes, L., Silverman, J.L., Leblond, C.S., … Crawley, J.N. (2012). Absence of deficits in social behaviors and ultrasonic vocalizations in later generations of mice lacking neuroligin4. Genes, Brain, & Behavior, (Epub ahead of print).

Leblond, C.S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., … Bourgeron, T. (2012). Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genetics, 8, e1002521.

Nava, C., Lamari, F., Héron, D., Mignot, C., Rastetter, A., Keren, B., … Depienne, C. (2012). Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. Translational Psychiatry, 2, e179.

Pinel, P., Fauchereau, F., Moreno, A., Barbot, A., Lathrop, M., Zelenika, D., … Dehaene, S. (2012). Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions. Journal of Neuroscience, 32, 817-825.

Sato, D., Lionel, A.C., Leblond, C.S., Prasad, A., Pinto, D., Walker, S., … Scherer, S.W. (2012). SHANK1 Deletions in Males with Autism Spectrum Disorder. American Journal of Human Genetics, 90, 879-887.

Schmeisser, M.J., Ey, E., Wegener, S., Bockmann, J., Stempel, A.V., Kuebler, A., … Boeckers, T.M. (2012). Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature, 486, 256-260.

Amaral, D., Rogers, S.J., Baron-Cohen, S., Bourgeron, T., Caffo, E., Fombonne, E., … van der Gaag, R.J. (2011). Against le packing: a consensus statement. Journal of the American Academy of Child and Adolescent Psychiatry, 50, 191-192.

Chaste, P., Clement, N., Botros, H.G., Guillaume, J.L., Konyukh, M., Pagan, C., … Bourgeron, T. (2011). Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders. Journal of Pineal Research, 51, 394-399.

Ey, E., Leblond, C.S., & Bourgeron, T. (2011). Behavioral profiles of mouse models for autism spectrum disorders. Autism Research, 4, 5-16.

Konyukh, M., Delorme, R., Chaste, P., Leblond, C., Lemière, N., Nygren, G., … Bourgeron, T. (2011). Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations. PLoS One, 6, e17289.

Pagan, C., Botros, H.G., Poirier, K., Dumaine, A., Jamain, S., Moreno, S., … Bourgeron, T. (2011). Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability. BMC Medical Genetics, 12, 17.

Poot, M., van der Smagt, J.J., Brilstra, E.H., & Bourgeron, T. (2011). Disentangling the myriad genomics of complex disorders, specifically focusing on autism, epilepsy, and schizophrenia. Cytogenetic Genome Research, 135, 228-240.

Anney, R., Klei, L., Pinto, D., Regan, R., Conroy, J., Magalhaes, T.R., … Hallmayer, J. (2010). A genome-wide scan for common alleles affecting risk for autism. Human Molecular Genetics, 19, 4072-4082.

Chaste, P., Clement, N., Mercati, O., Guillaume, J.L., Delorme, R., Botros, H.G., … Bourgeron, T. (2010). Identification of pathway-biased and deleterious melatonin receptor mutants in autism spectrum disorders and in the general population. PLoS One, 5, e11495.

Delorme, R., Betancur, C., Scheid, I., Anckarsäter, H., Chaste P., Jamain, S., … Bourgeron T. (2010). Mutation screening of NOS1AP gene in a large sample of psychiatric patients and controls. BMC Medical Genetics, 11, 108.

Delorme, R., Betancur, C., Chaste, P., Kernéis, S., Stopin, A., Mouren, M.C., … Launay, J.M. (2010). Reduced 3-O-methyl-dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 153B, 542-548.

Pinto, D., Pagnamenta, A.T., Klei, L., Anney, R., Merico, D., Regan, R., … Betancur, C. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466, 368-372.

Toro, R., Konyukh, M., Delorme, R., Leblond, C., Chaste, P., Fauchereau, F., … Bourgeron, T. (2010). Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends in Genetics, 26, 363-372.

Jamain, S., Radyushkin, K., Hammerschmidt, K., Granon, S., Boretius, S., Varoqueaux, F., … Brose, N. (2008). Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proceedings of the National Academy of Sciences of the United States of America, 105, 1710-1715.

Melke, J., Goubran Botros, H., Chaste, P., Betancur, C., Nygren, G., Anckarsäter, H., … Bourgeron, T. (2008). Abnormal melatonin synthesis in autism spectrum disorders. Molecular Psychiatry, 13, 90-98.

Autism Genome Project Consortium, Szatmari, P., Paterson, A.D., Zwaigenbaum, L., Roberts, W., Brian, J., … Meyer, K.J. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319-328.

Durand, C.M., Betancur, C., Boeckers, T.M., Bockmann, J., Chaste, P., Fauchereau, F., … Bourgeron, T. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics, 39, 25-27.

Belmonte, M.K., & Bourgeron, T. (2006). Fragile X syndrome and autism at the intersection of genetic and neural networks. Nature Neuroscience 9, 1221-1225.

Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I.C., … Bourgeron, T. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27-29.

Page Manager: Anna Spyrou|Last update: 1/21/2013

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