Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

Nord, Alexander; Roeb, Wendy; Dickel, Diane E.; Walsh, Tom; Kusenda, Mary; O’Connor, Kristen Lewis; Malhotra, Dheeraj; McCarthy, Shane; Stray, Sunday M.; Taylor, Susan; Sebat, Jonathan; King, Bryan H.; King, Mary Claire; McClellan, Jon

doi:10.1038/ejhg.2011.24

Cited by 113 publications

(80 citation statements)

References 28 publications

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“…There were no additional CNV calls in any of the family members, which strongly suggests a modifier of unknown origin as previously reported in thrombocytopenia-absent radius syndrome (OMIM 274000) [Klopocki et al, 2007]. There may be a smaller CNV occurring elsewhere in the genome, below the resolution detected by Affymetrix arrays, and conferring a transcription-related, neurodevelopmental or receptor function that exacerbates the effect of the 17q12 deletion in the offspring [Nord et al, 2011]. Alternatively, there may be a relatively common variant or polymorphism which acts as trigger.…”

Section: Discussionsupporting

confidence: 69%

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum

George¹,

Love²,

Hayes

et al. 2011

Mol Syndromol

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The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition.

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Section: Discussionsupporting

confidence: 69%

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum

George¹,

Love²,

Hayes

et al. 2011

Mol Syndromol

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“…20 Finally, an autistic patient was identified carrying a deletion of an putative upstream promoter region, which resulted in reduced expression levels. 21 Thus, although these deletions do not interrupt the protein product, they may affect regulatory elements to produce altered functional levels of CNTNAP2.…”

Section: Cntnap2 and Cognitive Disorders Mutations Of Cntnap2mentioning

confidence: 99%

Shining a light on CNTNAP2: complex functions to complex disorders

2013

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The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

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“…More recently, we have found that loss of GluD1 produces molecular phenotypes relevant to autism and developmental delay, including impaired dendritic spine pruning and switch in N-methyl-D-aspartate (NMDA) receptor GluN2B to the GluN2A subunit in the hippocampus and prefrontal cortex (Grossman et al, 2006;Penzes et al, 2011;Swanger et al, 2011;Gupta et al, 2015). Indeed, singlenucleotide polymorphism and copy-number variation studies have identified the GRID1 gene, which codes for GluD1, as a susceptibility gene for autism, schizophrenia, bipolar disorder, and major depression (Fallin et al, 2005;Glessner et al, 2009;Smith et al, 2009;Greenwood et al, 2011;Nord et al, 2011;Edwards et al, 2012;Griswold et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

et al. 2016

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The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the N-methyl-D-aspartate receptor subunit, which are relevant to autism and other neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer, which regulates mechanistic target of rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and protein kinase B, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts with mGlu5, and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function.

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Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

Cited by 113 publications

References 28 publications

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum

Shining a light on CNTNAP2: complex functions to complex disorders

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

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