DPYSL2 maps to 8p21 and encodes a highly conserved phosphoprotein, CRMP2, which plays key roles in the specification and growth of axons. CRMP2 is a member of the DISC1 interactome and also binds microtubules and functions as a cargo receptor to traffic certain essential proteins (e.g. tubulin heterodimers, the SRA1-WAVE1 complex and others) towards the growing end of the developing axon. CRMP2 function has also shown to be involved in the endocytosis of neural adhesion molecules in the axon growth cone and semaphorin 3A mediated growth cone collapse. Evidence from several sources including genomewide linkage and association scans, candidate gene association studies and from our preliminary studies on the functional consequences of sequence variants all implicate certain DPYSL2 variants as conferring risk for schizophrenia (SZ). Also, our preliminary data indicate that certain of the variants confer a sex-specific risk for SZ and relate expression of DPYSL2 variants to mTOR signaling and environmental variables. Thus, these rare genetic variants suggest a mechanism for relating environmental factors such as perinatal stress to risk for SZ. In this proposal we will perform additional large scale sequencing studies to develop an exhaustive catalog of DPYSL2 variants and we will then determine the functional consequences of these perturbations in DPYSL2/CRMP2 function. To accomplish the latter, we will produce and characterize a conditional mouse model for loss of DPYSL2 function. We will also develop cellular and zebrafish systems to test the functional consequences of DPYSL2 variants. Finally, we will explore the role of mTOR signaling in regulating the expression of DPYSL2 at the level of translation and how this is perturbed by certain DPYSL2 variants. As we identify and understand functional variants in DPYSL2, we will also relate this information to the extensive catalog of phenotypic differences of our rigorously characterized SZ patient sample.
Strong genetic and biologic evidence implicates variants in the DPYSL2 gene as conferring risk for SZ. We intend to expand the list of risk alleles and understand the mechanisms by which these genetic variants increase risk for SZ. Our preliminary results suggest that the risk conferred by variation in DPYSL2 function depends on the sex of the subject and interacts with environmental variables known to be associated with increased risk for SZ.
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