title: Mouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.
abstract: The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia.
  
  
  CONCLUSIONS
  Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Kogan
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Gross
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Featherstone
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Rick
authors.initials: R
authors.lastname: Shin
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Heusner
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Noah M
authors.initials: NM
authors.lastname: Walton
authors.affiliation: Bioimaging Research, Translational Science Research Labs, and.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyake
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tajinda
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
authors.affiliation: Neuroscience, Astellas Research Institute of America LLC, Skokie, Illinois 60077, Neuroscience Research Unit, Research Portfolio and Science, Drug Discovery Research, Astellas Pharma, Inc., Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan, and mitsuyuki.matsumoto@astellas.com.
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology; D001245:Association Learning / Q000502:physiology; D000067877:Autism Spectrum Disorder / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006120:Grooming / Q000502:physiology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007398:Interpersonal Relations; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010862:Pilocarpine / Q000494:pharmacology; D012640:Seizures / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D012903:Smell / Q000502:physiology; D014828:Vocalization, Animal / Q000502:physiology
chemical_list: D010862:Pilocarpine
keywords: 15q13.3; CNV; autism; epilepsy; intellectual disability; schizophrenia