title: The 15q13.3 deletion syndrome: Deficient α(7)-containing nicotinic acetylcholine receptor-mediated neurotransmission in the pathogenesis of neurodevelopmental disorders.
abstract: Array comparative genomic hybridization (array CGH) has led to the identification of microdeletions of the proximal region of chromosome 15q between breakpoints (BP) 3 or BP4 and BP5 encompassing CHRNA7, the gene encoding the α7-nicotinic acetylcholine receptor (α7nAChR) subunit. Phenotypic manifestations of persons with these microdeletions are variable and some heterozygous carriers are seemingly unaffected, consistent with their variable expressivity and incomplete penetrance. Nonetheless, the 15q13.3 deletion syndrome is associated with several neuropsychiatric disorders, including idiopathic generalized epilepsy, intellectual disability, autism spectrum disorders (ASDs) and schizophrenia. Haploinsufficient expression of CHRNA7 in this syndrome has highlighted important roles the α7nAChR plays in the developing brain and normal processes of attention, cognition, memory and behavior throughout life. Importantly, the existence of the 15q13.3 deletion syndrome contributes to an emerging literature supporting clinical trials therapeutically targeting the α7nAChR in disorders such as ASDs and schizophrenia, including the larger population of patients with no evidence of haploinsufficient expression of CHRNA7. Translational clinical trials will be facilitated by the existence of positive allosteric modulators (PAMs) of the α7nAChR that act at sites on the receptor distinct from the orthosteric site that binds acetylcholine and choline, the receptor's endogenous ligands. PAMs lack intrinsic efficacy by themselves, but act where and when the endogenous ligands are released in response to relevant social and cognitive provocations to increase the likelihood they will result in α7nAChR ion channel activation.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507-1912, United States. Electronic address: deutscsi@evms.edu.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Deutsch
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507-1912, United States.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Burket
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507-1912, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Benson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507-1912, United States.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Urbano
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000188:drug therapy / Q000503:physiopathology*; D002884:Chromosomes, Human, Pair 15; D006801:Humans; D008607:Intellectual Disability / Q000188:drug therapy / Q000503:physiopathology*; D065886:Neurodevelopmental Disorders / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D018722:Nicotinic Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: 15q13.3 deletion; Autism spectrum disorder; Copy number variation; Positive allosteric modulator; Schizophrenia; α(7)-Containing nicotinic acetylcholine receptor