A rare polymorphism affects a mitogen-activated protein kinase site in synapsin III: possible relationship to schizophrenia.
BACKGROUND
Synapsin III plays a role in neuronal plasticity and maps to chromosome 22q12-13, a region suggested to be linked to schizophrenia. To determine if synapsin III plays a role in this disease, we searched for polymorphisms in this gene in patients with schizophrenia and controls.


METHODS
The synapsin III gene was initially sequenced from 10 individuals with schizophrenia to identify polymorphisms. Association analysis was then performed using 118 individuals with schizophrenia and 330 population controls. Synapsin III expression was studied by immunoblot analyses, and phosphorylation sites were mapped by sequencing trypsin-digested synapsin III fragments phosphorylated with phosphorus-32.


RESULTS
A rare, missense polymorphism, S470N, was identified in the synapsin III gene and appeared more frequently in individuals with schizophrenia than in controls (p =.0048). The site affected by the polymorphism, Ser470, was determined to be a substrate for mitogen-activated protein kinase, a downstream effector of neurotrophin action. Phosphorylation at Ser470 was increased during neonatal development and in response to neurotrophin-3 in cultured hippocampal neurons.


CONCLUSIONS
Our observations suggest an association of a rare polymorphism in synapsin III with schizophrenia, but further studies will be required to clarify its role in this disease.
Porton
Barbara
B
Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA.
Ferreira
Adriana
A
DeLisi
Lynn E
LE
Kao
Hung Teh
HT
D000818:Animals; D000831:Animals, Newborn; D001216:Asparagine / Q000235:genetics; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005192:Family Health; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007930:Leucine / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011233:Precipitin Tests / Q000379:methods; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics*; D020539:Sequence Analysis, Protein; D012694:Serine / Q000235:genetics; D016704:Synapsins
D004791:Enzyme Inhibitors; D009479:Neuropeptides; D010750:Phosphoproteins; C111812:SYN3 protein, human; D016704:Synapsins; D012694:Serine; D001216:Asparagine; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D007930:Leucine