<p> Many neurologic diseases cause discrete episodic impairment. Study of the genes and mechanisms underlying these diseases has informed our understanding of the nervous system. Here we describe a novel episodic neurologic disorder, which we term familial cortical myoclonus (FCM). FCM is characterized by adult onset, slowly progressive, multifocal, cortical myoclonus, inherited as an autosomal dominant trait. On the basis of clinical, electrophysiological, and genetic data, FCM is nosologically distinct. We utilized genome-wide single nucleotide polymorphism genotyping, microsatellite linkage, and massively parallel sequencing to identify a mutation in the <i>gene <u> n</u>ucle<u>ol</u>ar protein 3</i> (<i> NOL3</i>) that likely causes FCM. <i>NOL3</i> is thought to bind to pro-apoptotic proteins and thereby repress apoptosis, but our extensive experimentation did not replicate these claims. In vitro, the <i>NOL3 </i> mutation leads to post-translational modification of NOL3 protein. We could not pinpoint the identity of the modification, but did find that this process is regulated by phosphorylation at residue T114. Finally, a proteomic screen for novel binding partners identified two candidates that modulate neuronal/astroglial differentiation. We hypothesize that the <i>NOL3 </i> mutation abrogates these interactions to cause FCM. This hypothesis will be tested with <i>Nol3</i> mutant mice that we generated. In total, this work defines a novel episodic neurologic phenotype and the associated mutation, calls into question some of the published functions of <i> NOL3,</i> and presents an alternative mechanism that may explain the pathophysiology of FCM.</p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:3558440 |
| Date | 05 June 2013 |
| Creators | Russell, Jonathan Foster |
| Publisher | University of California, San Francisco |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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