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J Tarabeux,
O Kebir,
J Gauthier,
F F Hamdan,
L Xiong,
A Piton,
D Spiegelman,
Eacute]| Henrion,
B Millet,
F Fathalli, [......], L E DeLisi,
Eacute]| Fombonne,
L Mottron,
N Forget-Dubois,
M Boivin,
J L Michaud,
P Drapeau,
R G Lafreni|[egrave]|re,
G A Rouleau,
M-O Krebs
[show abstract]
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ABSTRACT: Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.Keywords: autism; mutation; NMDA; schizophrenia
Translational Psychiatry. 10/2011; 1(11):e55.
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A Piton,
J Gauthier,
F F Hamdan,
R G Lafrenière,
Y Yang,
E Henrion,
S Laurent,
A Noreau,
P Thibodeau,
L Karemera, [......],
P Cossette,
M-O Krebs,
J L Rapoport,
A Addington, L E Delisi,
L Mottron,
R Joober,
E Fombonne,
P Drapeau,
G A Rouleau
[show abstract]
[hide abstract]
ABSTRACT: Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).
Molecular psychiatry 08/2011; 16(8):867-80. · 15.05 Impact Factor
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C Francks,
S Maegawa,
J Laurén,
B S Abrahams,
A Velayos-Baeza,
S E Medland,
S Colella,
M Groszer,
E Z McAuley,
T M Caffrey, [......],
G A Rouleau,
J F Stein,
M Karayiorgou,
D H Geschwind,
J Ragoussis,
K S Kendler,
M S Airaksinen,
M Oshimura, L E DeLisi,
A P Monaco
[show abstract]
[hide abstract]
ABSTRACT: Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We found significant association of a haplotype upstream of the gene LRRTM1 (Leucine-rich repeat transmembrane neuronal 1) with a quantitative measure of human handedness in a set of dyslexic siblings, when the haplotype was inherited paternally (P=0.00002). While we were unable to find this effect in an epidemiological set of twin-based sibships, we did find that the same haplotype is overtransmitted paternally to individuals with schizophrenia/schizoaffective disorder in a study of 1002 affected families (P=0.0014). We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.
Molecular Psychiatry 01/2008; 12(12):1129-39, 1057. · 13.67 Impact Factor
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C Francks,
S Maegawa,
J Laurén,
B S Abrahams,
A. Velayos-Baeza,
S. E. Medland,
S Colella,
M Groszer,
E. Z. McAuley,
T. M. Caffrey, [......],
G A Rouleau,
J F Stein,
M Karayiorgou,
D H Geschwind,
J Ragoussis,
K S Kendler,
M S Airaksinen,
M Oshimura, L E DeLisi,
A P Monaco
Molecular Psychiatry 01/2007; 12:1057. · 13.67 Impact Factor
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C Francks,
S Maegawa,
J. Lauren,
B S Abrahams,
A. Velayos-Baeza,
S. E. Medland,
S Colella,
Matthias Groszer,
E. Z. McAuley,
T. M. Caffrey, [......],
G A Rouleau,
J F Stein,
M Karayiorgou,
D H Geschwind,
J Ragoussis,
K S Kendler,
M S Airaksinen,
M Oshimura, L E DeLisi,
A P Monaco
Molecular Psychiatry, v.12, 1129-1139 (2007).
