The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. In addition, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/- mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.
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Ballif BC, Theisen A, Coppinger J, Gowans GC, Hersh JH, Madan-Khetarpal S, et al. Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet. 2008;1:8.
Glassford MR, Rosenfeld JA, Freedman AA, Zwick ME, Mulle JG, Unique Rare Chromosome Disorder Support G. Novel features of 3q29 deletion syndrome: results from the 3q29 registry. Am J Med Genet A. 2016;170A:999–1006.
Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49:27–35.
Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010;87:229–36.
Mulle JG, Gambello MJ, Cook EH, Rutkowski TP, Glassford M. 3q29 recurrent deletion. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle, WA; University of Washington, Seattle; 1993–2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK385289/.
Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87:1215–33.
Willatt L, Cox J, Barber J, Cabanas ED, Collins A, Donnai D, et al. 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet. 2005;77:154–60.
Grozeva D, Conrad DF, Barnes CP, Hurles M, Owen MJ, O’Donovan MC, et al. Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia. Schizophr Res. 2012;135:1–7.
Mulle JG. The 3q29 deletion confers >40-fold increase in risk for schizophrenia. Mol Psychiatry. 2015;20:1028–9.
Korablev AN, Serova IA, Serov OL. Generation of megabase-scale deletions, inversions and duplications involving the Contactin-6 gene in mice by CRISPR/Cas9 technology. BMC Genet. 2017;18(Suppl 1):112.
Carroll LS, Williams HJ, Walters J, Kirov G, O’Donovan MC, Owen MJ. Mutation screening of the 3q29 microdeletion syndrome candidate genes DLG1 and PAK2 in schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:844–9.
Rutkowski TP, Schroeder JP, Gafford GM, Warren ST, Weinshenker D, Caspary T, et al. Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders. J Neurosci Res. 2017;95:1144–60.
Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW. SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit. J Biol Chem. 1998;273:19518–24.
Purcell SM, Moran JL, Fromer M, Ruderfer D, Solovieff N, Roussos P, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–90.
Uezato A, Kimura-Sato J, Yamamoto N, Iijima Y, Kunugi H, Nishikawa T. Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia. Behav Brain Funct. 2012;8:2.
Toyooka K, Iritani S, Makifuchi T, Shirakawa O, Kitamura N, Maeda K, et al. Selective reduction of a PDZ protein, SAP-97, in the prefrontal cortex of patients with chronic schizophrenia. J Neurochem. 2002;83:797–806.
Gupta P, Uner OE, Nayak S, Grant GR, Kalb RG. SAP97 regulates behavior and expression of schizophrenia risk enriched gene sets in mouse hippocampus. PLoS ONE. 2018;13:e0200477.
Wang Y, Zeng C, Li J, Zhou Z, Ju X, Xia S, et al. PAK2 haploinsufficiency results in synaptic cytoskeleton impairment and autism-related behavior. Cell Rep. 2018;24:2029–41.
Grice SJ, Liu JL, Webber C. Synergistic interactions between Drosophila orthologues of genes spanned by de novo human CNVs support multiple-hit models of autism. PLoS Genet. 2015;11:e1004998.
Mahoney ZX, Sammut B, Xavier RJ, Cunningham J, Go G, Brim KL, et al. Discs-large homolog 1 regulates smooth muscle orientation in the mouse ureter. Proc Natl Acad Sci USA. 2006;103:19872–7.
Yang M, Silverman JL, Crawley JN. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 2011;Chapter 8: Unit 8 26.
Chalermpalanupap T, Schroeder JP, Rorabaugh JM, Liles LC, Lah JJ, Levey AI, et al. Locus coeruleus ablation exacerbates cognitive deficits, neuropathology, and lethality in P301S tau transgenic mice. J Neurosci. 2018;38:74–92.
Weinshenker D, Miller NS, Blizinsky K, Laughlin ML, Palmiter RD. Mice with chronic norepinephrine deficiency resemble amphetamine-sensitized animals. Proc Natl Acad Sci USA. 2002;99:13873–7.
R-CoreTeam. A language and environment for statistical computing. Vienna, Austria: R foundation for Statistical Computing; 2017. http://www.R-project.org.
Bates D, Machler M, Bolker BM, Walker SC. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67:1–48.
Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest package: tests in linear mixed effects models. J Stat Softw. 2017;82:1–26.
Cox DM, Butler MG. A clinical case report and literature review of the 3q29 microdeletion syndrome. Clin Dysmorphol. 2015;24:89–94.
Nielsen J, Fejgin K, Sotty F, Nielsen V, Mork A, Christoffersen CT, et al. A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission. Transl Psychiatry. 2017;7:1261.
Takahashi H, Nakamura T, Kim J, Kikuchi H, Nakahachi T, Ishitobi M, et al. Acoustic hyper-reactivity and negatively skewed locomotor activity in children with autism spectrum disorders: an exploratory study. Front Psychiatry. 2018;9:355.
Kesby JP, Eyles DW, McGrath JJ, Scott JG. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry. 2018;8:30.
Paval D. A dopamine hypothesis of autism spectrum disorder. Dev Neurosci. 2017;39:355–60.
Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, Graves T, et al. Mapping and sequencing of structural variation from eight human genomes. Nature. 2008;453:56–64.
Logue SF, Paylor R, Wehner JM. Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task. Behav Neurosci. 1997;111:104–13.
Morris RG, Hagan JJ, Rawlins JN. Allocentric spatial learning by hippocampectomised rats: a further test of the “spatial mapping” and “working memory” theories of hippocampal function. Q J Exp Psychol B. 1986;38:365–95.
Baez-Mendoza R, Schultz W. The role of the striatum in social behavior. Front Neurosci. 2013;7:233.
Koch M. The neurobiology of startle. Prog Neurobiol. 1999;59:107–28.
Murphy MM, Lindsey Burrell T, Cubells JF, Espana RA, Gambello MJ, Goines KCB, et al. Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome. BMC Psychiatry. 2018;18:183.
Halladay AK, Bishop S, Constantino JN, Daniels AM, Koenig K, Palmer K, et al. Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol Autism. 2015;6:36.
Kirkovski M, Enticott PG, Fitzgerald PB. A review of the role of female gender in autism spectrum disorders. J Autism Dev Disord. 2013;43:2584–603.
Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.
Prendergast BJ, Onishi KG, Zucker I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev. 2014;40:1–5.
The work was supported by R01GM097331 (TC, DW, and STW), R56MH116994 (TC, JGM, DW, and STW) and R01MH110701 along with funds from the Department of Human Genetics at Emory. This study was supported in part by the Mouse Transgenic and Gene Targeting Core (TMF) and the Rodent Behavioral Core, which are subsidized by the Emory University School of Medicine and are part of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical and Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. We are grateful to Dr. Jeffrey Miner, Washington University in St Louis, for providing Dlg1 mutant mice. This study was also supported by the Emory Winship Research Pathology Core Lab.
GJB, TC, JGM, STW, and DW designed the research. TPR, RHP, and RMP performed research with help from GMG, SMG, UAK, RMP, TM, and JPS. MPE, TPR, and RMP analyzed data. TC, JGM, TPR, and DW wrote the manuscript. All authors provided edits and approved final manuscript.
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Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome