A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability

Mosca-Boidron, Anne-Laure; Gueneau, Lucie; Huguet, Guillaume; Goldenberg, Alice; Henry, Céline; Gigot, Nadège; Pallesi-Pocachard, Emilie; Falace, Antonio; Duplomb, Laurence; Thévenon, Julien; Duffourd, Yannis; St‐Onge, Judith; Chambon, Pascal; Rivière, Jean‐Baptiste; Thauvin‐Robinet, Christel; Callier, Patrick; Marle, Nathalie; Payet, Muriel; Ragon, Clémence; Botros, Hany Goubran; Buratti, Julien; Caldérari, Sophie; Dumas, Guillaume; Delorme, Richard; Lagarde, Nathalie; Pinoit, Jean-Michel; Rosier, Antoine; Masurel‐Paulet, Alice; Cardoso, Carlos; Mugneret, Francine; Saugier-Veber, Pascale; Campion, Dominique; Faivre, Laurence; Bourgeron, Thomas

doi:10.1038/ejhg.2015.211

Cited by 42 publications

(44 citation statements)

References 35 publications

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“…In addition to PLXNA2 , mutations in SEMA5A ( Mosca-Boidron et al, 2016 ; Weiss et al, 2009 ), RAP1 ( Stornetta and Zhu, 2011 ), and CXCL12/CXCR4 ( Toritsuka et al, 2013 ) associate with increased risk for neuropsychiatric illness. Of interest, the scaffold protein Shank3 negatively regulates integrin-mediated cell adhesion by binding Rap1 and, thereby, sequestering it away from the plasma membrane ( Lilja et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

et al. 2018

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SUMMARYDentate gyrus (DG) development requires specification of granule cell (GC) progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP) domain and Rap1 small GTPases. In adult Plxna2−/− but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2−/− mice revealed deficits in associative learning, sociability, and sensorimotor gating—traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2 and RAP1 associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health.

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Section: Discussionmentioning

confidence: 99%

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

et al. 2018

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“…During mouse postnatal development, Sema3F regulates excitatory synapse formation in apical dendrites of layer V pyramidal neurons, and loss of this signaling increases apical dendrite spine density and the excitability of these neurons (Demyanenko et al, 2014;Tran et al, 2009). In humans, semaphorin and plexin gene variants are associated with a number of neurodevelopmental disorders, including autism spectrum disorder (Cheng et al, 2013;Fujii et al, 2011;Kim et al, 2017;Mosca-Boidron et al, 2016;Wu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice

Assous

Martinez

Eisenberg

et al. 2019

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The striatum represents the main input structure of the basal ganglia, receiving massive excitatory input from the cortex and the thalamus. The development and maintenance of cortical input to the striatum is crucial for all striatal function including many forms of sensorimotor integration, learning and action control. The molecular mechanisms regulating the development and maintenance of corticostriatal synaptic transmission are unclear. Here we show that the guidance cue, Semaphorin 3F and its receptor Neuropilin 2 (Nrp2), influence dendritic spine maintenance, corticostriatal short-term plasticity, and learning in adult male and female mice. We found that Nrp2 is enriched in adult layer V pyramidal neurons, corticostriatal terminals, and in developing and adult striatal spiny projection neurons (SPNs). Loss of Nrp2 increases SPN excitability and spine number, reduces short-term facilitation at corticostriatal synapses, and impairs goal-directed learning in an instrumental task. Acute deletion of Nrp2 selectively in adult layer V cortical neurons produces a similar increase in the number of dendritic spines and presynaptic modifications at the corticostriatal synapse in the Nrp2 -/mouse, but does not affect the intrinsic excitability of SPNs. Furthermore conditional loss of Nrp2 impairs sensorimotor learning on the accelerating rotarod without affecting goal-directed instrumental learning. Collectively, our results identify Nrp2 signaling as essential for the development and maintenance of the corticostriatal pathway and may shed novel insights on neurodevelopmental disorders linked to the corticostriatal pathway and semaphorin signaling. Significance StatementThe corticostriatal pathway controls sensorimotor, learning and action control behaviors and its dysregulation is linked to neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here we demonstrate that neuropilin 2 (Nrp2), a receptor for the axon-guidance cue semaphorin 3F, has important and previously unappreciated functions in the development and adult maintenance of dendritic spines on striatal spiny projection neurons (SPNs), corticostriatal short-term plasticity, intrinsic physiological properties of SPNs and learning in mice. Our findings, coupled with Nrp2's association with ASD in human populations, suggest that Nrp2 may play an important role in ASD pathophysiology. Overall, our work demonstrates Nrp2 as a key regulator of corticostriatal development, maintenance and function, and may lead to better understanding of neurodevelopmental disease mechanisms.

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“…In the past few years three family based GWAS had identified potential autism susceptibility variants at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059), all expressed in brain. SEMA5A is an intriguing candidate gene for autism: a de novo microdeletion was reported in this gene in a patient with ASD and ID [Mosca‐Boidron et al, ], and it has been shown to regulate synaptogenesis in hippocampus [Duan et al, ]. The associated variant was suggested to have an impact on the expression of the SEMA5A gene, which was found downregulated in brains and lymphoblastoid cell lines of patients with ASD [Cheng, Quinn, & Weiss, ; Melin et al, ; Weiss et al, ].…”

Section: Discussionmentioning

confidence: 99%

“…All ASD patients met ICD‐10 or DSM‐IV TR criteria for autism, Asperger disorder or pervasive developmental disorder not otherwise specified (PDD‐NOS), assessed using ADI‐R (Autism‐Diagnostic Interview‐Revised) [Lord, Rutter, & Le Couteur, ] and when possible also ADOS (Autism Diagnostic Observation Schedule) [Lord et al, ]. Additional information about case and control samples for each country regarding recruitment, diagnostic approach and selection can be found in previous publications [Bacchelli et al, ; Mosca‐Boidron et al, ; Prandini et al, ; Toma et al, ; Torrico et al, ; van Steijn et al, ; Waltes et al, ]. In this study, ASD patients were considered high functioning if their IQ score was greater than 70.…”

Section: Methodsmentioning

confidence: 99%

Lack of replication of previous autism spectrum disorder GWAS hits in European populations

et al. 2016

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Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4141463 (2,855 ASD cases and 36,177 controls) and five European populations for rs4307059 (2,347 ASD cases and 2,764 controls). The results showed an odds ratio (OR) of 1.05 (95% CI = 0.84-1.32) for rs10513025, 1.0002 (95% CI = 0.93-1.08) for rs4141463 and 1.01 (95% CI = 0.92-1.1) for rs4307059, with no significant P-values (rs10513025, P = 0.73; rs4141463, P = 0.95; rs4307059, P = 0.9). No association was found when we considered either only high functioning autism (HFA), genders separately or only multiplex families. Ongoing GWAS projects with larger ASD cohorts will contribute to clarify the role of common variation in the disorder and will likely identify risk variants of modest effect not detected previously. Autism Res 2017, 10: 202-211. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

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A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability

Cited by 42 publications

References 35 publications

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

Neuropilin 2 signaling mediates corticostriatal transmission, spine maintenance, and goal-directed learning in mice

Lack of replication of previous autism spectrum disorder GWAS hits in European populations

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