Article

Clinically Relevant Single Gene or Intragenic Deletions Encompassing Critical Neurodevelopmental Genes in Patients With Developmental Delay, Mental Retardation, and/or Autism Spectrum Disorders

Department of Genetics, University of Alabama at Birmingham, 35294, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 10/2011; 155A(10):2386-96. DOI: 10.1002/ajmg.a.34177
Source: PubMed

ABSTRACT

Recent studies suggest that copy number variations (CNVs) encompassing several genes involved in neurodevelopmental pathways are associated with a variety of neuropsychiatric phenotypes, including developmental delay (DD), mental retardation (MR), and autism spectrum disorders (ASDs). Here we present eight patients in a cohort of approximately 1,200 patients referred for clinical array CGH testing for various neurodevelopmental phenotypes,whowere identified to carry small (<1.0Mb with the majority <500 kb) either total gene or intragenic deletions encompassing critical synaptic and other neurodevelopmental genes. The presentations of these patients included variable degrees of DD, speech problems, learning disabilities, MR, autistic-like features, and mild non-specific dysmorphic features. These genes belong to four functional categories, including neuronal transcription factor genes (NFIA at 1p31.3, MEF2C at 5q14.3, andCAMAT1at 1p36.23p36.31), neuron-specific splicing factor genes (RBFOX1 at 16p13.2p13.3), genes involved in synapse formation and maintenance (CNTNAP2 at 7q35 and LRFN5 at 14q21.2), and genes involved in neurotransmission (CHRNA7 at 15q13.3 and IL1RAPL1 at Xp21.2p21.3). Our report expands the list of neurodevelopmental genes deleted in various neurobehavioral phenotypes, expands the phenotypes caused by haploinsufficiency of previously reported critical neurodevelopmental genes, and elucidates the clinical relevance and need for careful clinical interpretation of some small CNVs<500 kb. This report also suggests that small clinically relevant deletions encompassing critical synaptic and other neurodevelopmental genes can present clinically with various neurobehavioral phenotypes, which implies the existence of overlapping neuronal pathways in the pathogenesis of these phenotypes.

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    • "It should also be noted that a metabolite of GTS-21 has weak activity at 5-HT 3 receptors [57], so the current study cannot rule out off-target effects. a7 nAChRs are implicated in multiple neuropsychiatric disorders that can feature comorbidity with aggressive behavior, including autism spectrum disorder [58] [59] [60], 15q13.3 microdeletion syndrome that frequently presents with autism and aggression [61] [62] [63] [64], schizophrenia [65], and attention deficit hyperactivity disorder [66]. "
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    ABSTRACT: Electrophysiological and neurochemical studies implicate cholinergic signaling in the basolateral amygdala in behaviors related to stress. Both animal studies and human clinical trials suggest that drugs that alter nicotinic acetylcholine receptor (nAChR) activity can affect behaviors related to mood and anxiety. Clinical studies also suggest that abnormalities in cholinergic signaling are associated with major depressive disorder, whereas pre-clinical studies have implicated both β2 subunit-containing (β2*) and α7 nAChRs in the effects of nicotine in models of anxiety- and depression-like behaviors. We therefore investigated whether nAChR signaling in the amygdala contributes to stress-mediated behaviors in mice. Local infusion of the non-competitive non-selective nAChR antagonist mecamylamine or viral-mediated down-regulation of the β2 or α7 nAChR subunit into the amygdala all induced robust anxiolytic- and antidepressant-like effects in several mouse behavioral models. Further, whereas α7 nAChR subunit knockdown was somewhat more effective at decreasing anxiety-like behavior, only β2 subunit knockdown decreased resilience to social defeat stress and c-fos immunoreactivity in the basolateral amygdala. In contrast, α7, but not β2, subunit knockdown effectively reversed the effect of increased ACh signaling in a mouse model of depression. These results suggest that signaling through β2* nAChRs is essential for baseline excitability of the basolateral amygdala, and a decrease in signaling through β2 nAChRs alters anxiety- and depression-like behaviors even in unstressed animals. In contrast, stimulation of α7 nAChRs by acetylcholine may mediate the increased depression-like behaviors observed during the hypercholinergic state observed in depressed individuals.Neuropsychopharmacology accepted article preview online, 16 October 2015. doi:10.1038/npp.2015.316.
    Full-text · Article · Oct 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "It should also be noted that a metabolite of GTS-21 has weak activity at 5-HT 3 receptors [57], so the current study cannot rule out off-target effects. a7 nAChRs are implicated in multiple neuropsychiatric disorders that can feature comorbidity with aggressive behavior, including autism spectrum disorder [58] [59] [60], 15q13.3 microdeletion syndrome that frequently presents with autism and aggression [61] [62] [63] [64], schizophrenia [65], and attention deficit hyperactivity disorder [66]. "
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    DESCRIPTION: Background: Aggressive behavior often complicates the treatment of many neuropsychiatric disorders, especially neurodevelopmental and neurodegenerative disorders. Levels and signaling of nicotinic acetylcholine receptors (nAChRs) are altered in many of these conditions. Previous studies have demonstrated that acute administration of nicotine can reduce aggression in animal models. We therefore hypothesized that pharmacological agents active at specific nAChR subunits might be therapeutic for aggression occurring in these conditions. To that end, we sought to identify the molecular basis for nicotine’s anti-aggressive (“serenic”) effect, and to characterize the effects of GTS-21, an α7 nAChR partial agonist, on aggression in mouse models. Methods: Aggressive behavior was quantified using socially-isolated adult male C57BL/6 and BALB/c mice in a resident-intruder paradigm. Nicotine or GTS-21 was administered i.p. 10 minutes prior to initiation of resident-intruder tests. Antagonists (DHβE, 3 mg/kg, or MLA, 5 mg/kg) were administered i.p. 15 minutes prior to nicotine or GTS-21. Social interaction and locomotor testing was performed using a Noldus EthovisionXT system. c-Fos expression was quantified as a marker of neuronal activity. Results: As previously reported, aggressive behavior was dose-dependently reduced by nicotine administration, with the serenic effect of a moderate dose (0.25 mg/kg) eliminated by the α7 nAChR antagonist MLA but not by the heteromeric nAChR antagonist DHβE. We further found dose-dependent serenic effects of the α7 nAChR partial agonist GTS-21 in BALB/c mice, a low sociability and moderately aggressive mouse strain. GTS-21 was further evaluated to identify its effects on locomotor activity, sociability with conspecifics, and regulation of neuronal activity in brain regions important for regulation of aggression. Conclusion: Selective activation of the α7 nAChR may be a promising therapeutic avenue for reducing aggressive behavior. Furthermore, as multiple α7 nAChRs agonists are well tolerated in human subjects, efficacy in humans with pathological aggression can be tested in controlled clinical trials.
    Full-text · Poster · Oct 2015
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    • "It should also be noted that a metabolite of GTS-21 has weak activity at 5-HT 3 receptors [57], so the current study cannot rule out off-target effects. a7 nAChRs are implicated in multiple neuropsychiatric disorders that can feature comorbidity with aggressive behavior, including autism spectrum disorder [58] [59] [60], 15q13.3 microdeletion syndrome that frequently presents with autism and aggression [61] [62] [63] [64], schizophrenia [65], and attention deficit hyperactivity disorder [66]. "
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    ABSTRACT: Aggression is frequently comorbid with neuropsychiatric conditions and is a predictor of worse outcomes, yet current pharmacotherapies are insufficient and have debilitating side effects, precluding broad use. Multiple models of aggression across species suggest that the nicotinic acetylcholine receptor (nAChR) agonist nicotine has anti-aggressive (serenic) properties. Here we demonstrate dose-dependent serenic effects of acute nicotine administration in three distinct mouse strains: C57BL/6, BALB/c, and CD1. While acute nicotine administration (0.25mg/kg) modestly reduced solitary homecage locomotion, this could not account for nicotine's serenic effects since social encounters eliminated the hypolocomotor effect, and nicotine did not alter social interaction times. Pretreatment with the homomeric (α7 subunit) nAChR antagonist methyllycaconitine (5mg/kg), but not the heteromeric (β2 or β4 subunit-containing) nAChR antagonist dihydro-β-erythroidine (DHβE, 3mg/kg), blocked the serenic effects of nicotine. By contrast, pretreatment with DHβE blocked the effect of acute nicotine administration on locomotion, uncoupling nicotine's serenic and hypolocomotor effects. Finally, the α7 nAChR partial agonist GTS-21 reduced aggression in C57BL/6 mice. These results support the idea that acute nicotine administration has serenic effects and provide evidence for specificity of this effect distinct from effects on locomotion. Furthermore, pharmacological studies suggest that activation of α7 nAChRs underlies the serenic effects of nicotine. Further studies of nAChRs could enhance understanding of the neurobiology of aggression and may lead to the development of novel, more specific treatments for pathological aggression. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Biochemical pharmacology
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