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The Levinson Emerging Scholars Program

Molly Gasperini - Biochemistry and Chemistry

Molly GasperiniBoth biology and issues of mental health have interested Molly since she was in high school. For the past two years, she has been able to work in both of these fields as she investigates a mutation in the DNA of a patient with schizophrenia. She has pursued this research under the mentorship of Dr. Mary-Claire King, in the departments of Medical Genetics and Genome Sciences, and Caitlin Rippey, a graduate student in the UW's Medical Scientist Training MD/PhD Program. With the support of the Levinson Scholarship, Molly hopes to complete her analysis of this mutation and contribute to the understanding of the biological mechanisms of schizophrenia. This research experience, combined with her biology major and experience in activism for mental health awareness, has inspired her to pursue graduate school and a career in neurogenetics research.

Mentor: Mary-Claire King, Genome Sciences and Medicine

Project Title: Biological characterization of a genetic mutation implicated in schizophrenia

Abstract: Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences continue to be elusive. Rare, gene-disrupting genomic deletions and duplications called copy number variants (CNVs) have been implicated in schizophrenia; however, much remains to be understood about which genes are causative, as well as the cellular mechanisms involved. Biological follow up on individual CNVs will give insight to the origin of schizophrenia. We focused on one that duplicates the 5' ends of two genes that lie head-to-head on chromosome 11q22: DCUN1D5, a previously uncharacterized gene predicted to be involved in cullin neddylation of ubiquitin ligase complexes, and DYNC2H1, a dynein active in cilia. Both are expressed in brain and are plausible candidate genes for schizophrenia. Using RNAseq, we detected novel DCUN1D5 transcripts that we predict will result in truncated DCUN1D5 protein in the patient's cells. In order to understand the function of DCUN1D5, we will determine which of seven possible cullin binding partners it interacts with using an in vitro neddylation assay. We will then test the conformational stability of truncated DCUN1D5 by Western blot in the patient's cells and transfected cell lines. We will then be able to compare the function of the full length DCUN1D5 with the aberrant DCUN1D5 present in the patient. Investigation of these aberrant proteins may shed light on pathways that contribute to schizophrenia, potentially guiding the search for new candidate genes and the development of novel treatment strategies.