Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR

Abstract

Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype–phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Volkmar FR, Pauls D . Autism. Lancet 2003; 362: 1133–1141.

    Article  PubMed  Google Scholar 

  2. Geschwind DH . Genetics of autism spectrum disorders. Trends Cogn Sci 2011; 15: 409–416.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 2009; 459: 569–573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 2010; 19: 4072–4082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009; 459: 528–533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weiss LA, Arking DE . Gene Discovery Project of Johns H, the Autism C, Daly MJ, Chakravarti A . A genome-wide linkage and association scan reveals novel loci for autism. Nature 2009; 461: 802–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237–241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485: 246–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485: 242–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G et al. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012; 8: e1002521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Baker P, Piven J, Schwartz S, Patil S . Brief report: duplication of chromosome 15q11-13 in two individuals with autistic disorder. J Autism Dev Disord 1994; 24: 529–535.

    Article  CAS  PubMed  Google Scholar 

  13. Dykens EM, Sutcliffe JS, Levitt P . Autism and 15q11-q13 disorders: behavioral, genetic, and pathophysiological issues. Ment Retard Dev Disabil Res Rev 2004; 10: 284–291.

    Article  PubMed  Google Scholar 

  14. Bolton PF, Veltman MW, Weisblatt E, Holmes JR, Thomas NS, Youings SA et al. Chromosome 15q11-13 abnormalities and other medical conditions in individuals with autism spectrum disorders. Psychiatr Genet 2004; 14: 131–137.

    Article  PubMed  Google Scholar 

  15. Vorstman JA, Staal WG, van Daalen E, van Engeland H, Hochstenbach PF, Franke L . Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 2006; 11: 18–28.

    Article  CAS  Google Scholar 

  16. Cook EH Jr., Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C et al. Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 1997; 60: 928–934.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang Y, Tsai TF, Bressler J, Beaudet AL . Imprinting in Angelman and Prader-Willi syndromes. Curr Opin Genet Dev 1998; 8: 334–342.

    Article  CAS  PubMed  Google Scholar 

  18. Locke DP, Segraves R, Nicholls RD, Schwartz S, Pinkel D, Albertson DG et al. BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications. J Med Genet 2004; 41: 175–182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bittel DC, Kibiryeva N, Butler MG . Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in Prader-Willi syndrome. Pediatrics 2006; 118: e1276–e1283.

    Article  PubMed  Google Scholar 

  20. Butler MG, Bittel DC, Kibiryeva N, Talebizadeh Z, Thompson T . Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Pediatrics 2004; 113 (3 Pt 1): 565–573.

    Article  PubMed  Google Scholar 

  21. Meguro-Horike M, Yasui DH, Powell W, Schroeder DI, Oshimura M, Lasalle JM et al. Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Hum Mol Genet 2011; 20: 3798–3810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C et al. A copy number variation morbidity map of developmental delay. Nat Genet 2011; 43: 838–846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chaste P, Sanders SJ, Mohan KN, Klei L, Song Y, Murtha MT et al. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2. Autism Res 2014; 7: 355–362.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet 2011; 130: 517–528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV et al. A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. Am J Med Genet 2010; 153B: 960–966.

    PubMed  Google Scholar 

  26. de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C et al. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133 (Pt 1): 23–32.

    Article  PubMed  Google Scholar 

  27. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 2014; 505: 361–366.

    Article  CAS  PubMed  Google Scholar 

  28. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schenck A, Bardoni B, Moro A, Bagni C, Mandel JL . A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc Natl Acad Sci USA 2001; 98: 8844–8849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rogers SJ, Wehner DE, Hagerman R . The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr 2001; 22: 409–417.

    Article  CAS  PubMed  Google Scholar 

  31. Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 2007; 16: 1682–1698.

    Article  CAS  PubMed  Google Scholar 

  32. Nowicki ST, Tassone F, Ono MY, Ferranti J, Croquette MF, Goodlin-Jones B et al. The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr 2007; 28: 133–138.

    Article  PubMed  Google Scholar 

  33. Schenck A, Bardoni B, Langmann C, Harden N, Mandel JL, Giangrande A . CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein. Neuron 2003; 38: 887–898.

    Article  CAS  PubMed  Google Scholar 

  34. Napoli I, Mercaldo V, Boyl PP, Eleuteri B, Zalfa F, De Rubeis S et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 2008; 134: 1042–1054.

    Article  CAS  PubMed  Google Scholar 

  35. Kobayashi K, Kuroda S, Fukata M, Nakamura T, Nagase T, Nomura N et al. p140Sra-1 (specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase. J Biol Chem 1998; 273: 291–295.

    Article  CAS  PubMed  Google Scholar 

  36. De Rubeis S, Pasciuto E, Li KW, Fernandez E, Di Marino D, Buzzi A et al. CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 2013; 79: 1169–1182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang XW, Gong S . An overview on the generation of BAC transgenic mice for neuroscience research. Curr Protoc Neurosci 2005; Chapter 5, Unit 5 20.

  38. Yang XW, Model P, Heintz N . Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nat Biotechnol 1997; 15: 859–865.

    Article  CAS  PubMed  Google Scholar 

  39. Galun M, Basri R, Brandt A . Multiscale edge detection and fiber enhancement using differences of oriented means. ICCV 2007; (IEEE 11th International Conference on): 1–8.

  40. Irwin SA, Idupulapati M, Gilbert ME, Harris JB, Chakravarti AB, Rogers EJ et al. Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am J Med Genet 2002; 111: 140–146.

    Article  PubMed  Google Scholar 

  41. McKinney BC, Grossman AW, Elisseou NM, Greenough WT . Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am J Med Genet B Neuropsychiatr Genet 2005; 136B: 98–102.

    Article  PubMed  Google Scholar 

  42. Irwin SA, Patel B, Idupulapati M, Harris JB, Crisostomo RA, Larsen BP et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 2001; 98: 161–167.

    Article  CAS  PubMed  Google Scholar 

  43. Geschwind DH, Sowinski J, Lord C, Iversen P, Shestack J, Jones P et al. The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. Am J Hum Genet 2001; 69: 463–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI et al. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 2009; 5: e1000536.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wintle RF, Lionel AC, Hu P, Ginsberg SD, Pinto D, Thiruvahindrapduram B et al. A genotype resource for postmortem brain samples from the Autism Tissue Program. Autism Res 2011; 4: 89–97.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 2011; 474: 380–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abrahams BS, Tentler D, Perederiy JV, Oldham MC, Coppola G, Geschwind DH . Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc Natl Acad Sci USA 2007; 104: 17849–17854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Oguro A, Kubota H, Shimizu M, Ishiura S, Atomi Y . Protective role of the ubiquitin binding protein Tollip against the toxicity of polyglutamine-expansion proteins. Neurosci Lett 2011; 503: 234–239.

    Article  CAS  PubMed  Google Scholar 

  49. Coppola G, Marmolino D, Lu D, Wang Q, Cnop M, Rai M et al. Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARgamma pathway as a therapeutic target in Friedreich's ataxia. Hum Mol Genet 2009; 18: 2452–2461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Coppola G . Designing, performing, and interpreting a microarray-based gene expression study. Methods Mol Biol 2011; 793: 417–439.

    Article  CAS  PubMed  Google Scholar 

  51. Edgar R, Domrachev M, Lash AE . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 2002; 30: 207–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hutsler JJ, Zhang H . Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 2010; 1309: 83–94.

    Article  CAS  PubMed  Google Scholar 

  53. Ran I, Gkogkas CG, Vasuta C, Tartas M, Khoutorsky A, Laplante I et al. Selective regulation of GluA subunit synthesis and AMPA receptor-mediated synaptic function and plasticity by the translation repressor 4E-BP2 in hippocampal pyramidal cells. J Neurosci 2013; 33: 1872–1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Galvez R, Greenough WT . Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome. Am J Med Genet A 2005; 135: 155–160.

    Article  PubMed  Google Scholar 

  55. Grossman AW, Aldridge GM, Weiler IJ, Greenough WT . Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. J Neurosci 2006; 26: 7151–7155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Osterweil EK, Krueger DD, Reinhold K, Bear MF . Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J Neurosci 2010; 30: 15616–15627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005; 42: 318–321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR, Leech JM et al. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 2012; 488: 647–651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Grossman AW, Elisseou NM, McKinney BC, Greenough WT . Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines. Brain Res 2006; 1084: 158–164.

    Article  CAS  PubMed  Google Scholar 

  60. Xiong Q, Oviedo HV, Trotman LC, Zador AM . PTEN regulation of local and long-range connections in mouse auditory cortex. J Neurosci 2012; 32: 1643–1652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dudanova I, Tabuchi K, Rohlmann A, Sudhof TC, Missler M . Deletion of alpha-neurexins does not cause a major impairment of axonal pathfinding or synapse formation. J Comp Neurol 2007; 502: 261–274.

    Article  CAS  PubMed  Google Scholar 

  62. Dahlhaus R, Hines RM, Eadie BD, Kannangara TS, Hines DJ, Brown CE et al. Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus. Hippocampus 2010; 20: 305–322.

    Article  CAS  PubMed  Google Scholar 

  63. De Rubeis S, Bagni C . Regulation of molecular pathways in the Fragile X Syndrome: insights into Autism Spectrum Disorders. J Neurodev Disord 2011; 3: 257–269.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 2011; 146: 247–261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Comery TA, Harris JB, Willems PJ, Oostra BA, Irwin SA, Weiler IJ et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci USA 1997; 94: 5401–5404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, Murphy JP, Pierre P, Klann E . Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 2012; 76: 325–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Varga EA, Pastore M, Prior T, Herman GE, McBride KL . The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med 2009; 11: 111–117.

    Article  PubMed  Google Scholar 

  68. Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V . Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet 2009; 75: 195–198.

    Article  CAS  PubMed  Google Scholar 

  69. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 2006; 50: 377–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kwon CH, Zhu X, Zhang J, Baker SJ . mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci USA 2003; 100: 12923–12928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Goto J, Talos DM, Klein P, Qin W, Chekaluk YI, Anderl S et al. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. Proc Natl Acad Sci USA 2011; 108: E1070–E1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Carson RP, Van Nielen DL, Winzenburger PA, Ess KC . Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin. Neurobiol Dis 2011; 45: 369–380.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Pathania M, Davenport EC, Muir J, Sheehan DF, Lopez-Domenech G, Kittler JT . The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines. Transl Psychiatry 2014; 4: e374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bozdagi O, Sakurai T, Dorr N, Pilorge M, Takahashi N, Buxbaum JD . Haploinsufficiency of cyfip1 produces fragile x-like phenotypes in mice. PLoS ONE 2012; 7: e42422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Golzio C, Willer J, Talkowski ME, Oh EC, Taniguchi Y, Jacquemont S et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 2012; 485: 363–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hammond P, McKee S, Suttie M, Allanson J, Cobben JM, Maas SM et al. Opposite effects on facial morphology due to gene dosage sensitivity. Hum Genet 2014; 133: 1117–1125.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Jacquemont S, Reymond A, Zufferey F, Harewood L, Walters RG, Kutalik Z et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 2011; 478: 97–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rosenfeld JA, Kim KH, Angle B, Troxell R, Gorski JL, Westemeyer M et al. Further evidence of contrasting phenotypes caused by reciprocal deletions and duplications: duplication of NSD1 causes growth retardation and microcephaly. Mol Syndromol 2013; 3: 247–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Van der Aa N, Rooms L, Vandeweyer G, van den Ende J, Reyniers E, Fichera M et al. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 2009; 52: 94–100.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the UCLA transgenic mice core for injection of Cyfip1 Bac transgenic mice; Drs William Yang, Xiaofeng Gu, Paul Mischel, Akio Iwanami, Eric Wexler, Yoshitake Sano, Genevieve Konopka, Ezra Rosen and Luis de la Torre Ubieta for helpful discussions in planning the experiments; Drs Jeff Goodenbour, Jason Stein, Irina Voineagu, Olga Peñagarikano for important experimental advice and support; Greg Osborn, Hongmei Dong and Camille Fonseca for technical assistance and Lauren Kawaguchi for manuscript editing. This work was supported by funds from the Uehara Memorial Foundation (AO-A), Japan Society for the Promotion of Science (AO-A) and a New Investigator Development Award, a Human Genetics Pilot Award and a Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (P30HD071593) Pilot Award from the Albert Einstein College of Medicine (BSA) and grants from the NIH (R37 MH60233-06A1, R01 MH081754-02R to DHG).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D H Geschwind.

Ethics declarations

Competing interests

The authors declare no conflict of interest. A provisional patent describing the potential utility of mTOR inhibitors in individuals with ASD harboring 15q11-13 duplications has been filed.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oguro-Ando, A., Rosensweig, C., Herman, E. et al. Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR. Mol Psychiatry 20, 1069–1078 (2015). https://doi.org/10.1038/mp.2014.124

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.124

This article is cited by

Search

Quick links