title: Reduced CYFIP1 in Human Neural Progenitors Results in Dysregulation of Schizophrenia and Epilepsy Gene Networks.
abstract: Deletions encompassing the BP1-2 region at 15q11.2 increase schizophrenia and epilepsy risk, but only some carriers have either disorder. To investigate the role of CYFIP1, a gene within the region, we performed knockdown experiments in human neural progenitors derived from donors with 2 copies of each gene at the BP1-2 locus. RNA-seq and cellular assays determined that knockdown of CYFIP1 compromised cytoskeletal remodeling. FMRP targets and postsynaptic density genes, each implicated in schizophrenia, were significantly overrepresented among differentially expressed genes (DEGs). Schizophrenia and/or epilepsy genes, but not those associated with randomly selected disorders, were likewise significantly overrepresented. Mirroring the variable expressivity seen in deletion carriers, marked between-line differences were observed for dysregulation of disease genes. Finally, a subset of DEGs showed a striking similarity to known epilepsy genes and represents novel disease candidates. Results support a role for CYFIP1 in disease and demonstrate that disease-related biological signatures are apparent prior to neuronal differentiation.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Nebel
authors.affiliation: Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Dejian
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Pedrosa
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jill
authors.initials: J
authors.lastname: Kirschen
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Lachman
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Abrahams
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D002884:Chromosomes, Human, Pair 15; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017384:Sequence Deletion
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C109916:CYFIP1 protein, human; D009419:Nerve Tissue Proteins
references.citation: Nature. 2008 Sep 11;455(7210):232-6
references.pmid: 18668039
references.citation: PLoS One. 2014;9(4):e94968
references.pmid: 24736721
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9962-7
references.pmid: 23716668
references.citation: Bioinformatics. 2015 Jan 15;31(2):166-9
references.pmid: 25260700
references.citation: Am J Med Genet A. 2015 Sep;167A(9):2098-102
references.pmid: 25946043
references.citation: Cell. 2012 Mar 16;148(6):1223-41
references.pmid: 22424231
references.citation: Circulation. 2013 Mar 5;127(9):1009-17
references.pmid: 23388215
references.citation: Cell. 2008 Sep 19;134(6):1042-54
references.pmid: 18805096
references.citation: Hum Mol Genet. 2011 Nov 15;20(22):4381-94
references.pmid: 21852245
references.citation: Theory Biosci. 2012 Dec;131(4):281-5
references.pmid: 22872506
references.citation: Mol Psychiatry. 2013 Oct;18(10):1067-76
references.pmid: 23732879
references.citation: PLoS One. 2015;10(4):e0124597
references.pmid: 25905630
references.citation: PLoS One. 2013;8(3):e59685
references.pmid: 23536886
references.citation: Mol Autism. 2013 Oct 03;4(1):36
references.pmid: 24090431
references.citation: PLoS One. 2011;6(9):e23356
references.pmid: 21915259
references.citation: Schizophr Bull. 2013 May;39(3):712-9
references.pmid: 22317777
references.citation: N Engl J Med. 2012 Oct 4;367(14):1321-31
references.pmid: 22970919
references.citation: Nat Med. 2011 Dec;17(12):1657-62
references.pmid: 22120178
references.citation: J Med Genet. 2004 Oct;41(10):784-9
references.pmid: 15466014
references.citation: PLoS One. 2011;6(2):e17073
references.pmid: 21364941
references.citation: Genome Biol. 2010;11(10):R106
references.pmid: 20979621
references.citation: Development. 2004 Aug;131(16):3981-9
references.pmid: 15269173
references.citation: Hum Genet. 2011 Oct;130(4):517-28
references.pmid: 21359847
references.citation: Parkinsonism Relat Disord. 2009 Jun;15(5):390-2
references.pmid: 18824390
references.citation: Mol Psychiatry. 2015 Mar;20(3):361-8
references.pmid: 24686136
references.citation: Mol Cell Biol. 2004 Sep;24(17):7758-68
references.pmid: 15314181
references.citation: Am J Hum Genet. 1990 Mar;46(3):428-33
references.pmid: 2137962
references.citation: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W305-11
references.pmid: 19465376
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Brain. 2010 Jan;133(Pt 1):23-32
references.pmid: 19843651
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8844-9
references.pmid: 11438699
references.citation: Gene. 2014 Apr 1;538(2):323-7
references.pmid: 24440288
references.citation: Neuron. 2010 Oct 21;68(2):192-5
references.pmid: 20955926
references.citation: Nat Neurosci. 2011 Jan;14(1):19-21
references.pmid: 21170055
references.citation: Nature. 2014 Feb 13;506(7487):179-84
references.pmid: 24463507
references.citation: Genome Biol. 2013;14(4):R36
references.pmid: 23618408
references.citation: Am J Psychiatry. 2010 Apr;167(4):388-96
references.pmid: 19917593
references.citation: Autism Res. 2014 Jun;7(3):355-62
references.pmid: 24821083
references.citation: PLoS One. 2015;10(7):e0132387
references.pmid: 26173148
references.citation: Cell. 1996 Feb 9;84(3):371-9
references.pmid: 8608590
references.citation: PLoS One. 2012;7(8):e42422
references.pmid: 22900020
references.citation: Curr Biol. 2003 Oct 28;13(21):1867-75
references.pmid: 14588242
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10584-9
references.pmid: 20489179
references.citation: Cell. 2010 Nov 12;143(4):527-39
references.pmid: 21074045
references.citation: Genes Brain Behav. 2009 Mar;8(2):129-42
references.pmid: 19016890
references.citation: PLoS One. 2012;7(8):e44017
references.pmid: 22952857
references.citation: Eur J Med Genet. 2009 Mar-Jun;52(2-3):108-15
references.pmid: 19328872
references.citation: Nature. 2012 May 10;485(7397):242-5
references.pmid: 22495311
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: Neuron. 2013 Sep 18;79(6):1169-82
references.pmid: 24050404
references.citation: Mol Med Rep. 2014 Apr;9(4):1242-8
references.pmid: 24566726
references.citation: Science. 1998 Jan 23;279(5350):509-14
references.pmid: 9438836
references.citation: Nat Rev Neurosci. 2010 Aug;11(8):539-51
references.pmid: 20648061
references.citation: Neuron. 2003 Jun 19;38(6):887-98
references.pmid: 12818175
references.citation: Mol Psychiatry. 2015 May;20(5):573-84
references.pmid: 25623948
references.citation: Mol Autism. 2014 Aug 20;5:44
references.pmid: 25694803
references.citation: Transl Psychiatry. 2014;4:e374
references.pmid: 24667445
references.citation: Nature. 2014 Feb 13;506(7487):185-90
references.pmid: 24463508
references.citation: Cell Stem Cell. 2014 Jul 3;15(1):79-91
references.pmid: 24996170
references.citation: Cell. 2004 Oct 1;119(1):19-31
references.pmid: 15454078
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4468-77
references.pmid: 25294932
references.citation: J Neurogenet. 2011 Oct;25(3):88-103
references.pmid: 21797804
references.citation: Biol Psychiatry. 2015 Sep 15;78(6):e29-34
references.pmid: 25708228
references.citation: Mol Psychiatry. 2015 Jun;20(6):703-17
references.pmid: 25733313
references.citation: Hum Genet. 2014 May;133(5):651-9
references.pmid: 24337656
references.citation: J Neurosci. 2014 Mar 12;34(11):3826-40
references.pmid: 24623762
references.citation: Mol Neuropsychiatry. 2015 Jul;1(2):116-123
references.pmid: 26528485
references.citation: Autism Res. 2011 Feb;4(1):40-56
references.pmid: 21268289
references.citation: Neurochem Res. 2008 Feb;33(2):248-56
references.pmid: 18058230
references.citation: Nature. 2014 Jan 16;505(7483):361-6
references.pmid: 24352232
references.citation: Mol Psychiatry. 2015 Sep;20(9):1069-78
references.pmid: 25311365