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 gene nucleolar protein 3 ( NOL3) that likely causes FCM. NOL3 is thought to bind to pro-apoptotic proteins and thereby repress apoptosis, but our extensive experimentation did not replicate these claims. In vitro, the NOL3 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 NOL3 mutation abrogates these interactions to cause FCM. This hypothesis will be tested with Nol3 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 NOL3, and presents an alternative mechanism that may explain the pathophysiology of FCM.
|Advisor:||Nussbaum, Robert L.|
|Commitee:||Ptacek, Louis J., Shannon, Kevin M.|
|School:||University of California, San Francisco|
|School Location:||United States -- California|
|Source:||DAI-B 74/08(E), Dissertation Abstracts International|
|Keywords:||Familial cortical myoclonus, Human genetics, Massively parallel sequencing, Myoclonus, Nol3|
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