Kellie Schaefer and Tyson Fuller Present at Genetics Student Seminar 5/22/17

Kellie A. Schaefer, Wen-Hsuan Wu, Stephen H. Tsang, Alexander G. Bassuk, Vinit B. Mahajan
Mutation of the calcium-activated protease calpain-5 (CAPN5) can cause a severe blinding disease, Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). In their twenties, ADNIV patients begin to display a synaptic signaling defect and intraocular inflammation (uveitis). Over the ensuing five decades, they experience retinal degeneration, retinal neovascularization, and intraocular fibrosis, culminating in phthisis and blindness. Although CAPN5 is expressed in many tissues, ADNIV patients only manifest disease in the eye. ADNIV CAPN5 is hyperactive, since the disease allele reduces the calcium level required for protease activity. Thus, the eye-restricted phenotype likely reflects the extraordinarily high calcium concentrations in the retina, where such a hyperactive calcium-dependent protease could be particularly damaging. To further study ADNIV disease progression we used CRISPR/Cas to create a mouse model.


TD Fuller1,2, AN Marsden1,2, Das T1, JM Hermosillo1, TA Westfall1, DC Slusarski1

1Department of Biology, University of Iowa, Iowa City, IA 52242, 2Interdisciplinary Graduate Program in Genetics

Epilepsy, which affects ~1% of the population, is caused by abnormal synchronous neural activity in the central nervous system (CNS). While there is a significant genetic contribution to epilepsy, the underlying causes for the majority of genetic cases remain unknown. The NIH Undiagnosed Diseases Project (UDP) utilized exome sequencing to identify genetic variants in patients affected by various conditions with undefined etiology, including epilepsy. Confirming the functional relevance of the candidate genes identified by exome sequencing in a timely manner is crucial to translating exome data into clinically useful information. To this end, I developed a high throughput version of a seizure-sensitivity assay in zebrafish (Danio rerio) to rapidly evaluate candidate genes found by exome sequencing. This assay uses pentylenetetrazol (PTZ) to induce seizures in zebrafish larvae and the motility tracking software of the Zebrabox (Viewpoint Life Sciences) is utilized to record each larva’s total movement (cm). This generates massive data sets. Therefore, I developed an open access software, SEIZR (Studying Epilepsy In Zebrafish using R), to rapidly and efficiently analyze the data.  My project focuses on characterizing the functional role of fifteen genes in the NIH UDP for which mutations have been associated with epilepsy, and for which zebrafish orthologues have been identified. Using SEIZR, I characterized all fifteen candidate genes in the context of seizure sensitization. Here, I show the findings of two genes, syne1b and zfhx3, both of which result in seizure sensitization when knocked down in the zebrafish. I show that each of these genes is expressed in regions of the brain involved in motor control during critical times of neural development. Further, I find syne1b knockdown results in axon defects in the retina.


Posted on May 15, 2017, in Student Seminar. Bookmark the permalink. Leave a comment.

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