De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.
Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.
Gauthier
Julie
J
Department of Medicine, Centre of Excellence in Neuromics of Université de Montréal, Centre Hospitalier de l'Université de Montréal Research Center, Université de Montréal, Montréal, QC H2L 2W5, Canada
Champagne
Nathalie
N
Lafrenière
Ronald G
RG
Xiong
Lan
L
Spiegelman
Dan
D
Brustein
Edna
E
Lapointe
Mathieu
M
Peng
Huashan
H
Côté
Mélanie
M
Noreau
Anne
A
Hamdan
Fadi F
FF
Addington
Anjené M
AM
Rapoport
Judith L
JL
Delisi
Lynn E
LE
Krebs
Marie-Odile
MO
Joober
Ridha
R
Fathalli
Ferid
F
Mouaffak
Fayçal
F
Haghighi
Ali P
AP
Néri
Christian
C
Dubé
Marie-Pierre
MP
Samuels
Mark E
ME
Marineau
Claude
C
Stone
Eric A
EA
Awadalla
Philip
P
Barker
Philip A
PA
Carbonetto
Salvatore
S
Drapeau
Pierre
P
Rouleau
Guy A
GA
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology*; D010375:Pedigree; D051381:Rats; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015027:Zebrafish
D002352:Carrier Proteins; D017931:DNA Primers; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C033652:postsynaptic density proteins
Psychol Med. 2010 Apr;40(4):547-56
19656427
Psychiatr Genet. 1995 Fall;5(3):127-30
8746411
Am J Med Genet. 1996 Feb 16;67(1):40-5
8678112
Science. 2003 Oct 31;302(5646):826-30
14593168
Prog Neurobiol. 2002 Oct;68(2):85-111
12450489
Schizophr Res. 2001 Aug 1;51(1):93-102
11479071
Neuron. 2001 Jul 19;31(1):115-30
11498055
Nature. 2008 Sep 11;455(7210):232-6
18668039
Clin Genet. 2007 Jun;71(6):599-601
17539913
Hum Mol Genet. 2008 Feb 1;17(3):458-65
17989066
Trends Neurosci. 2009 Jul;32(7):402-12
19541375
Bioinformatics. 2008 Oct 15;24(20):2397-8
18757876
Hum Mol Genet. 2001 Mar 15;10(6):591-7
11230178
J Comp Neurol. 1997 Oct 20;387(2):167-78
9336221
Nature. 1991 Jun 20;351(6328):652-4
1904993
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
12824425
Am J Hum Genet. 2007 Dec;81(6):1289-97
17999366
Psychol Med. 1997 Nov;27(6):1311-23
9403903
Biol Psychiatry. 2005 Jul 1;58(1):16-22
15992519
Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 5;150B(3):421-4
18615476
J Neurosci. 2005 Apr 6;25(14):3560-70
15814786
J Neurosci. 2008 Feb 13;28(7):1697-708
18272690
Am J Med Genet. 2002 Mar 8;114(2):245-52
11857589
Mol Cells. 2004 Apr 30;17(2):373-6
15179057
Mol Psychiatry. 2004 Aug;9(8):784-95
15007391
Nat Genet. 2008 Jul;40(7):880-5
18511947
Mol Biol Evol. 2007 Aug;24(8):1622-6
17478432
Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
12202775
Psychiatr Genet. 2007 Oct;17(5):292-8
17728668
Am J Psychiatry. 2002 May;159(5):803-12
11986135
Nucleic Acids Res. 2007;35(11):3823-35
17526529
Nature. 1999 Jan 28;397(6717):344-7
9950425
Schizophr Res. 1996 Sep 18;21(3):151-60
8885043
Am J Psychiatry. 2008 May;165(5):579-87
18413704
CNS Spectr. 2002 Jan;7(1):26-9
15254446
Mol Psychiatry. 2005 Jan;10(1):40-68; image 5
15263907
Nat Genet. 2007 Mar;39(3):319-28
17322880
Br J Psychiatry. 1999 Nov;175:444-51
10789276
Genet Epidemiol. 1990;7(1):3-16; discussion 17-45
2184091
Nat Genet. 2007 Jan;39(1):25-7
17173049
J Med Genet. 2003 Aug;40(8):575-84
12920066