Unit: Human Genetics and Cognitive Functions

Director: Bourgeron, Thomas

Our group is mainly interested in the genetic origin and evolution of human cognitive functions. To address these questions, we investigate the susceptibility to psychiatric syndromes such as autism, Obsessive-Compulsive Disorders (OCD), Attention Deficit Hyperactivity Disorder (ADHD), specific language disorder (SLI), and dyslexia. On the basis of linkage analyses and/or chromosomal rearrangements, we have characterised several candidate genes (FAM8A1, KIF13A, GRIK2, NLGNs) and identified the first mutations associated with idiopathic autism (neuroligins NLGN3 and NLGN4).

Our current research is focused on :

1. The role of synaptic genes in psychiatric disorders

2. The identification of genes involved in language disorders

Project 1. The role of synaptic genes in psychiatric disorders

Project 1A : The glutamate receptor GRIK2: Researchers : Jonas Melke, Richard Delorme, Hany Goubran-Botros

Several independent studies have shown a significant linkage between chromosome 6q16-q21 and autism, bipolar disorder and schizophrenia. Among the genes located in this region, we have studied the Glutamate Receptor Ionotropic Kainate 2 gene (GRIK2 or GluR6). We performed a linkage study, conducted with 59 sib-pairs families, which showed a significant excess of allele sharing in autistic children, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). Interestingly, maternal sharing was more pronounced than paternal sharing. The Transmission Disequilibrium Test (TDT), performed with all families plus an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (P = 0.0004). Mutation screening was performed on affected individuals, revealing several SNPs, including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GRIK2 is in association, or at least in linkage disequilibrium, with autism. These results were recently replicated by Shuang M et al. (AJMG, 2004) who found a transmission disequilibrium of GRIK2 in 174 Chinese Han parent-offspring trios with autism. Finally, we found a significant maternal transmission disequilibrium of the same GRIK2 haplotype in schizophrenia whereas, in OCD no association was observed. This project is continuing with the analysis of GRIK2 genetic variability and the functional studies of novel rare variations identified in patients with autism or schizophrenia.

Project 1B. Neuroligins and binding partners, Researchers : Christelle Durand, Richard Delorme, Hany Goubran-Botros.

A locus for susceptibility to autism and schizophrenia has been suggested on Xp22.3 by the observation of several independent de novo chromosomal rearrangements in patients with these disorders. Within this interval, we characterised the Neuroligin gene 4 (NLGN4), encoding a new member of the neuroligin family. These cell adhesion molecules, with homology to acetylcholine esterases, are crucial factors in the formation of functional synapses. In two brothers, one with autism and the other with Asperger syndrome, we identified a frame-shift mutation in NLGN4. This mutation (D396X) was localised in the esterase domain, leading to premature termination of the protein, before the trans-membrane domain. We also identified a non-synonymous mutation (R451C), which affects a highly conserved amino acid from the esterase domain of NLGN3 in two brothers, one with autism and the second with Asperger syndrome. Recently, additional NLGN4 mutations have been inditified in individuals with autism and mental retardation by two independent groups and ourselves, replicating the original results. Furthermore, the mutations (D396X and R451C) has been functionally analysed and found to cause abnormal synaptogenesis in cultured neurons. This project is continuing with the identification of additional mutations in NLGNs and their binding partners in order to have a better description of the functional deficits of synaptogenesis caused by these mutations to get a better description of the relationship between these mutations and the clinical phenotypes of the affected individuals.

Project 1C. Protocadherin PCDHX/Y ,Researcher: Christelle Durand

During the search for Y-linked genes associated with psychiatric disorders, we have studied the expression and the genetic variability of two closely related members of the protocadherin family PCDH11X/Y, located on the X and the Y chromosome, respectively. PCDH11Y is one of the rare genes specific to the hominoid lineage, absent in other primates. Expression analysis indicated that transcripts of the PCDH11X/Y genes are mainly detected in the cortex of the human brain. Mutation screening of thirty individuals with autism identified two PCDH11Y polymorphic amino acid changes, F885V and K980N. These variations are in complete association, appeared during human evolution approximately 40 000 years ago and represent informative polymorphisms to study Y chromosome variability in populations. We have studied the frequency of these variants in males with autism spectrum disorders, attention deficit hyper-activity disorder (ADHD), bipolar disorder, OCD and schizophrenia and observed no significant differences when patients were compared to geographically-matched control populations. These findings do not support the role of PCDH11Y, or more generally of a frequent specific Y chromosome, in the susceptibility to these neuropsychiatric disorders.

Project 1D. IMMP2L et NrCAM, Researcher: Richard Delorme

Tourettes Syndrome (TS) is characterised by involuntary motor and vocal tics, whereas OCD is characterised by recurrent, distressing unwanted thoughts and repetitive ritualistic behaviour. Both disorders have phenomenological and familial-genetic overlaps. Chromosome 7q31 has been implicated in both disorders by the presence of chromosomal rearrangements in probands with TS and OCD. Within 7q31, IMMP2L and NrCAM were suitable candidates for both disorders. Indeed, IMMP2L, disrupted in a duplication, has recently been shown to be associated with TS, while NrCAM is an important mediator with multiple effects on the development of the neurons. Mutation screening of the IMMP2L and NrCAM genes in individuals with TS and OCD was performed. In NrCAM, thirteen single nucleotide polymorphisms (SNPs) were identified including one non-synonymous change (A526P). Linkage disequilibrium was calculated and the most informative SNPs were genotyped in 100 additional OCD patients and 95 controls. Preliminary results indicate a significant difference in NrCAM haplotype frequencies in patients compared to controls (P=0.001). This study continues by screening additional SNPs and patients to further characterise the potential association between NrCAM and psychiatric disorders.

Project 2. Genes and language disorders. Responsable : Thomas Bourgeron

After exclusion of environmental causes (social, teaching, etc) or known biological diseases (deafness, mental retardation, etc), approximately 8 to 10% of school age children suffer from communication and language difficulties. While it is well established that genes are involved in the susceptibility to these disorders, no genetic study of dyslexia and specific language impairment (SLI) has ever been undertaken in France. This project brings together linguists, psychologists, psychiatrists, neurologists and geneticists around two common objectives: (1) To identify susceptibility genes and (2) to understand their role in the development of language and communication processes.

In this new project, we aim to study the genetics of language and communication disorders by identifying the genetic factors implicated in autism, SLI and dyslexia. This collaborative study links the laboratory of Human Genetics and Cognitive Function of the Pasteur Institute, three medical centres for developmental language disorders and the Paris Autism Research International Sib-pair consortium (PARIS). The priority for the first two years is the recruitment of families with at least two affected individuals and the mutation screening of candidate genes. In addition, an analysis of the chromosomes will be carried out, in all affected individuals, by high resolution karyotyping. In a second step, as soon as the critical number of families is reached (> 50 families for dyslexia and 50 for SLI), a whole genome scan will be performed. Finally, the relation between genes and cognition will be dissected by including a full cognitive battery and brain imaging measures.


In 2003, the identification of mutations in NLGN3 and NLGN4 sheds light on a physiological pathway (the synaptogenesis), which is different in individuals with autism or Asperger syndrome. In 2004, these results were replicated (by others and our group) and confirmed by functional studies in cultured neurons. Further analyses of the NLGNs, their binding partners and additional chromosomal rearrangements should give us a better view of the molecular pathways involved in the development of autism and related disorders. In 2005, we are initiating a new project on the genetics of SLI and dyslexia that could also give additional information on the genes associated with language and communication disorders in humans.

Keywords: autism, OCD, schizophrenia, language, genetics

Activity Reports 2004 - Institut Pasteur

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