title: Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice.
abstract: Autism spectrum disorders (ASDs) are a group of neurodevelopmental afflictions characterized by repetitive behaviors, deficits in social interaction, and impaired communication skills. For most ASD patients, the underlying causes are unknown. Genetic mutations have been identified in about 25 percent of ASD cases, including mutations in epigenetic regulators, suggesting that dysregulated chromatin or DNA function is a critical component of ASD. Mutations in the histone acetyltransferase CREB binding protein (CBP, CREBBP) cause Rubinstein-Taybi Syndrome (RTS), a developmental disorder that includes ASD-like symptoms. Recently, genomic studies involving large numbers of ASD patient families have theoretically modeled CBP and its paralog p300 (EP300) as critical hubs in ASD-associated protein and gene interaction networks, and have identified de novo missense mutations in highly conserved residues of the CBP acetyltransferase and CH1 domains. Here we provide animal model evidence that supports this notion that CBP and its CH1 domain are relevant to autism. We show that mice with a deletion mutation in the CBP CH1 (TAZ1) domain (CBPΔCH1/ΔCH1) have an RTS-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity. Our results therefore indicate that loss of CBP CH1 domain function contributes to RTS, and possibly ASD, and that this domain plays an essential role in normal motor function, cognition and social behavior. Although the key physiological functions affected by ASD-associated mutation of epigenetic regulators have been enigmatic, our findings are consistent with theoretical models involving CBP and p300 in ASD, and with a causative role for recently described ASD-associated CBP mutations.
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Lawryn H
authors.initials: LH
authors.lastname: Kasper
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Bedford
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lerach
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Brett J W
authors.initials: BJ
authors.lastname: Teubner
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105, United States of America.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001321:Autistic Disorder / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D001665:Binding Sites / Q000235:genetics; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000503:physiopathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D012919:Social Behavior
chemical_list: D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D051548:Histone Acetyltransferases