Neurocentre Magendie

Christelle DURAND





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Cursus:
2007 Ph.D. Human Genetics, Paris7.
2007-2010 Postdoc U862






12 publication(s) depuis Janvier 1990:


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01/2012 | Mol Psychiatry   IF 15
SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism.
Durand CM, Perroy J, Loll F, Perrais D, Fagni L, Bourgeron T, Montcouquiol M, Sans N

Abstract:
Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies.




2009 | BMC Med Genet   IF 2.1
An investigation of ribosomal protein L10 gene in autism spectrum disorders
Gong X, Delorme R, Fauchereau F, Durand C M, Chaste P, Betancur C, Goubran-Botros H, Nygren G, Anckarsater H, Rastam M, Gillberg I C, Kopp S, Mouren-Simeoni M C, Gillberg C, Leboyer M, Bourgeron T

Abstract:
BACKGROUND: Autism spectrum disorders (ASD) are severe neurodevelopmental disorders with the male:female ratio of 4:1, implying the contribution of X chromosome genetic factors to the susceptibility of ASD. The ribosomal protein L10 (RPL10) gene, located on chromosome Xq28, codes for a key protein in assembling large ribosomal subunit and protein synthesis. Two non-synonymous mutations of RPL10, L206M and H213Q, were identified in four boys with ASD. Moreover, functional studies of mutant RPL10 in yeast exhibited aberrant ribosomal profiles. These results provided a novel aspect of disease mechanisms for autism--aberrant processes of ribosome biosynthesis and translation. To confirm these initial findings, we re-sequenced RPL10 exons and quantified mRNA transcript level of RPL10 in our samples. METHODS: 141 individuals with ASD were recruited in this study. All RPL10 exons and flanking junctions were sequenced. Furthermore, mRNA transcript level of RPL10 was quantified in B lymphoblastoid cell lines (BLCL) of 48 patients and 27 controls using the method of SYBR Green quantitative PCR. Two sets of primer pairs were used to quantify the mRNA expression level of RPL10: RPL10-A and RPL10-B. RESULTS: No non-synonymous mutations were detected in our cohort. Male controls showed similar transcript level of RPL10 compared with female controls (RPL10-A, U = 81, P = 0.7; RPL10-B, U = 61.5, P = 0.2). We did not observe any significant difference in RPL10 transcript levels between cases and controls (RPL10-A, U = 531, P = 0.2; RPL10-B, U = 607.5, P = 0.7). CONCLUSION: Our results suggest that RPL10 has no major effect on the susceptibility to ASD.




05/09/2008 | Am J Med Genet B Neuropsychiatr Genet   IF 3.5
Analysis of X chromosome inactivation in autism spectrum disorders
Gong X, Bacchelli E, Blasi F, Toma C, Betancur C, Chaste P, Delorme R, Durand C M, Fauchereau F, Botros H G, Leboyer M, Mouren-Simeoni M C, Nygren G, Anckarsater H, Rastam M, Gillberg I C, Gillberg C, Moreno-De-Luca D, Carone S, Nummela I, Rossi M, Battaglia A, Jarvela I, Maestrini E, Bourgeron T

Abstract:
Autism spectrum disorders (ASD) are complex genetic disorders more frequently observed in males. Skewed X chromosome inactivation (XCI) is observed in heterozygous females carrying gene mutations involved in several X-linked syndromes. In this study, we aimed to estimate the role of X-linked genes in ASD susceptibility by ascertaining the XCI pattern in a sample of 543 informative mothers of children with ASD and in a sample of 163 affected girls. The XCI pattern was also determined in two control groups (144 adult females and 40 young females) with a similar age distribution to the mothers sample and affected girls sample, respectively. We observed no significant excess of skewed XCI in families with ASD. Interestingly, two mothers and one girl carrying known mutations in X-linked genes (NLGN3, ATRX, MECP2) showed highly skewed XCI, suggesting that ascertainment of XCI could reveal families with X-linked mutations. Linkage analysis was carried out in the subgroup of multiplex families with skewed XCI (> or = 80:20) and a modest increased allele sharing was obtained in the Xq27-Xq28 region, with a peak Z-score of 1.75 close to rs719489. In summary, our results suggest that there is no major X-linked gene subject to XCI and expressed in blood cells conferring susceptibility to ASD. However, the possibility that rare mutations in X-linked genes could contribute to ASD cannot be excluded. We propose that the XCI profile could be a useful criteria to prioritize families for mutation screening of X-linked candidate genes.




01/2008 | Med Sci (Paris)
[Alterations in synapsis formation and function in autism disorders]
Durand C M, Chaste P, Fauchereau F, Betancur C, Leboyer M, Bourgeron T

Abstract:





01/2008 | Mol Psychiatry   IF 15
Abnormal melatonin synthesis in autism spectrum disorders
Melke J, Goubran Botros H, Chaste P, Betancur C, Nygren G, Anckarsater H, Rastam M, Stahlberg O, Gillberg I C, Delorme R, Chabane N, Mouren-Simeoni M C, Fauchereau F, Durand C M, Chevalier F, Drouot X, Collet C, Launay J M, Leboyer M, Gillberg C, Bourgeron T

Abstract:
Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.






01/2007 | Nat Genet   IF 31.6
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders
Durand C M, Betancur C, Boeckers T M, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg I C, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni M C, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T

Abstract:
SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.




15/07/2006 | Biol Psychiatry   IF 8.9
No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects
Delorme R, Durand C M, Betancur C, Wagner M, Ruhrmann S, Grabe H J, Nygren G, Gillberg C, Leboyer M, Bourgeron T, Courtet P, Jollant F, Buresi C, Aubry J M, Baud P, Bondolfi G, Bertschy G, Perroud N, Malafosse A

Abstract:
BACKGROUND: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS: Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.




05/01/2006 | Am J Med Genet B Neuropsychiatr Genet   IF 3.5
Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders
Durand C M, Kappeler C, Betancur C, Delorme R, Quach H, Goubran-Botros H, Melke J, Nygren G, Chabane N, Bellivier F, Szoke A, Schurhoff F, Rastam M, Anckarsater H, Gillberg C, Leboyer M, Bourgeron T

Abstract:
Synaptogenesis, the formation of functional synapses, is a crucial step for the development of the central nervous system. Among the genes involved in this process are cell adhesion molecules, such as protocadherins and neuroligins, which are essential factors for the identification of the appropriate partner cell and the formation of synapses. In this work, we 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, being 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 30 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 studied the frequency of these variants in males with autism spectrum disorders (n = 110), attention deficit hyperactivity disorder (ADHD; n = 61), bipolar disorder (n = 61), obsessive-compulsive disorder (n = 51), or schizophrenia (n = 61) and observed no significant differences when compared to ethnically-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.




12/2005 | Mol Psychiatry   IF 15
Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive compulsive disorder
Delorme R, Betancur C, Wagner M, Krebs M O, Gorwood P, Pearl P, Nygren G, Durand C M, Buhtz F, Pickering P, Melke J, Ruhrmann S, Anckarsater H, Chabane N, Kipman A, Reck C, Millet B, Roy I, Mouren-Simeoni M C, Maier W, Rastam M, Gillberg C, Leboyer M, Bourgeron T

Abstract: