TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons.
TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Xavier
X
Caubit
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Paolo
P
Gubellini
Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France.
Joris
J
Andrieux
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Pierre L
PL
Roubertoux
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Mehdi
M
Metwaly
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Bernard
B
Jacq
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Ahmed
A
Fatmi
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Laurence
L
Had-Aissouni
Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.|Molecular & Behavioral Neuroscience Institute (MBNI), Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Kenneth Y
KY
Kwan
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Pascal
P
Salin
Aix Marseille Univ, CNRS, LPC, Marseille, France.
Michèle
M
Carlier
Karolinska University Hospital Solna, Clinical Genetics Unit, Stockholm, Sweden.
Agne
A
Liedén
Karolinska University Hospital Solna, Clinical Genetics Unit, Stockholm, Sweden.
Eva
E
Rudd
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Marwan
M
Shinawi
Service de Génétique clinique, Hôpital Jeanne de Flandre, CHRU Lille, France.
Catherine
C
Vincent-Delorme
Service de Neuropédiatrie, Hôpital Salengro, CHRU Lille, France.
Jean-Marie
JM
Cuisset
Service de Neuropédiatrie, Hôpital Salengro, CHRU Lille, France.
Marie-Pierre
MP
Lemaitre
Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France.
Fatimetou
F
Abderrehamane
Centre de cytogénétique, Hôpital Saint Vincent de Paul, GHICL, UCL, Lille, France.
Bénédicte
B
Duban
Centre de cytogénétique, Hôpital Saint Vincent de Paul, GHICL, UCL, Lille, France.
Jean-François
JF
Lemaitre
Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre and the Royal Manchester Children's and St Mary's Hospitals, Manchester, UK.
Adrian S
AS
Woolf
UCL Institute of Child Health, London, UK.
Detlef
D
Bockenhauer
MGX-Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, Montpellier, France.
Dany
D
Severac
MGX-Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, Montpellier, France.
Emeric
E
Dubois
Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Ying
Y
Zhu
Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Nenad
N
Sestan
Institute of Cell Biology and Neurobiology, Center for Anatomy, Charité University Hospital Berlin, Berlin, Germany.
Alistair N
AN
Garratt
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Goff
Goff
Lydia Kerkerian-Le
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Laurent
L
Fasano
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D002888:Chromosomes, Human, Pair 19; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D057895:Haploinsufficiency; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D019579:Neocortex / Q000196:embryology / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000473:pathology*; D013569:Synapses / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D018398:Homeodomain Proteins; C580600:TSHZ3 protein, human; C534111:Teashirt 3 protein, mouse; D014157:Transcription Factors
J Neurosci. 2013 Apr 24;33(17):7368-83
23616543
J Med Genet. 2013 Mar;50(3):163-73
23335808
Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17184-9
16284245
J Neurochem. 2016 Mar;136(5):1004-16
26576509
Nature. 2011 Apr 28;472(7344):437-42
21423165
Nature. 2011 Oct 26;478(7370):483-9
22031440
Neuron. 2008 Feb 7;57(3):378-92
18255031
J Physiol. 1991 Nov;443:533-53
1822537
J Comp Neurol. 2003 Mar 17;457(4):345-60
12561075
Science. 2012 Dec 21;338(6114):1619-22
23160955
Am J Med Genet A. 2014 Jan;164A(1):62-9
24243649
Neuron. 2005 Jan 20;45(2):207-21
15664173
Nat Methods. 2012 Mar 04;9(4):357-9
22388286
J Neurosci. 2008 Jan 16;28(3):622-32
18199763
J Neurosci. 2010 Jul 14;30(28):9465-76
20631175
Neuron. 2008 Jan 24;57(2):232-47
18215621
Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17792-7
16314561
Genes Brain Behav. 2004 Oct;3(5):303-14
15344923
PLoS One. 2009 Aug 10;4(8):e6568
19668335
Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):5052-6
22411800
Genome Biol. 2013 Apr 25;14(4):R36
23618408
Genet Med. 2010 Nov;12(11):694-702
20808228
Science. 2012 Sep 14;337(6100):1301-3
22984058
Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9397-402
18599437
Clin Genet. 2010 Nov;78(5):471-7
20412115
J Comp Neurol. 2005 May 23;486(1):76-88
15834955
Mol Autism. 2011 Jan 19;2(1):1
21247446
Development. 2012 May;139(9):1535-46
22492350
Cell. 2013 Nov 21;155(5):1008-21
24267887
Cell Rep. 2014 May 22;7(4):1077-92
24794428
G Ital Nefrol. 2015 ;32 Suppl 64:null
26479062
Neuron. 2012 Dec 20;76(6):1052-6
23259942
Am J Hum Genet. 2008 Jul;83(1):89-93
18571142
Am J Hum Genet. 2001 Aug;69(2):327-40
11452361
Alcohol Clin Exp Res. 2002 Oct;26(10):1502-11
12394283
Am J Med Genet A. 2012 May;158A(5):1170-7
22488896
Psychopharmacology (Berl). 2009 Jun;204(2):361-73
19189082
J Med Genet. 2009 Sep;46(9):635-40
19126570
Lancet. 2014 Mar 8;383(9920):896-910
24074734
Am J Med Genet. 1998 Jun 5;77(5):391-4
9632168
Pediatr Nephrol. 2010 Nov;25(11):2247-55
20603712
Nature. 2009 May 28;459(7246):528-33
19404256
Neuron. 2005 Sep 15;47(6):817-31
16157277
Nephrol Dial Transplant. 2010 Jan;25(1):54-60
19745106
Nat Rev Neurosci. 2013 Apr;14(4):278-91
23511908
PLoS One. 2010 Jan 01;5(1):e8550
20062544
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3555-60
23401504
Cereb Cortex. 2015 Oct;25(10 ):3406-19
25037921
Nucleic Acids Res. 2016 Jan 4;44(D1):D336-42
26578592
J Neurosci. 2010 Feb 10;30(6):2115-29
20147539
Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3041-6
21285371
Neuron. 1993 Jun;10(6):991-1006
8318235
Cell. 2013 Nov 21;155(5):997-1007
24267886
Psychopharmacology (Berl). 1977 May 9;52(3):271-7
406630
Development. 2008 Oct;135(19):3301-10
18776146
Dis Model Mech. 2010 Mar-Apr;3(3-4):133-5
20212079
J Neurosci. 2004 Oct 20;24(42):9228-31
15496656
Hum Mol Genet. 1998 Mar;7(3):571-8
9546821
Front Hum Neurosci. 2013 Aug 06;7:430
23964221
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):16021-6
18840685
Cereb Cortex. 2014 Feb;24(2):293-303
23118198
Genes Brain Behav. 2004 Oct;3(5):287-302
15344922
Curr Protoc Neurosci. 2009 Jul;Chapter 8:Unit 8.24
19575474
Brain Res Dev Brain Res. 1992 Jun 19;67(2):317-26
1511522
Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13129-34
20615956