The Codon Bias-Basis for Familial Dysautonomia: Project Summary Familial dysautonomia (FD) is a devastating and ultimately fatal neurodevelopmental and neurodegenerative disease characterized by an emaciated peripheral nervous system that is present at birth, as well as multiple debilitating conditions including blood pressure lability, tachycardia, unrelenting nausea and vomiting crises, progressive blindness, and chronic kidney disease. The lifespan of FD patients has increased significantly with more effective symptom management, however, patients still die during early adulthood. Although it has been known for some time that the mutated gene in FD, IKBKAP/ELP1 encodes the scaffolding protein for a multi-subunit complex called Elongator, the function of the Elongator complex and how the absence of this function translates into such a complex aftermath of effects has been an elusive and controversial area of investigation. Only recently have multiple studies converged on a consensus function for Elongator in the ability to interpret an aspect of the genetic code known as codon bias. The genetic code, used by all forms of life, includes multiple codons for the same amino acid. The reason for this redundancy remains poorly understood. However, new studies have shown that the preferential use of particular codons, or codon bias, can greatly impact the production rate of a given protein and hence the final levels of that protein within the cell. Although substantial strides have been made with regard to our understanding of codon bias and the function of Elongator in reading this bias, there is still an enormous disconnect with regard to how impairment of this basic function translates into the complex repercussions that comprise familial dysautonomia, as well as how mutations in other Elongator subunits contribute to other distinct neurological diseases including amyotrophic lateral sclerosis (ALS), Rolandic epilepsy, intellectual disability, and autism spectrum disorder. Our long-term goal is to make this connection; to identify the specific codon biased genes that depend on Elongator for normal expression levels and to characterize the downstream perturbed pathways that precipitate FD pathophysiology. Through the generation of a new mouse model, the included preliminary data demonstrate that deletion of Ikbkap in a single, isolated cell type in the anterior pituitary leads to a significant reduction in growth velocity, another hallmark feature of FD, and that this phenotype is likely due to the misregulation of a single codon-biased gene that regulates vesicle based secretion of growth hormone. Additional preliminary data indicate that codon bias likely contributes to the regulation of an enzymatic pathway controlling levels of the key neurotransmitters dopamine and norepinephrine. Accomplishment of the proposed specific aims will dramatically shift our understanding of the basic molecular and cellular mechanisms that go awry to precipitate FD and other neurological conditions associated with compromised Elongator function. As such, this proposal may also lead to the identification of new therapeutics for treating these devastating diseases.
The Codon Bias-Basis for Familial Dysautonomia: Project Narrative Familial Dysautonomia is a devastating and ultimately fatal neurodevelopmental and neurodegenerative disease caused by mutation in the gene IKBKAP/ELP1 that encodes an essential subunit of a large protein complex called Elongator. Mutations in other Elongator subunits are associated with multiple neurologic diseases including amyotrophic lateral sclerosis (ALS) and autism spectrum disorder. With the recent discovery of Elongator?s function in decoding an aspect of the genetic code known as codon bias, our goal is to identify specific codon-biased genes that are misregulated in the absence of Elongator and show directly how an impaired ability to interpret codon bias precipitates neurologic disease symptoms. ! !
| Lefcort, Frances; Mergy, Marc; Ohlen, Sarah B et al. (2017) Animal and cellular models of familial dysautonomia. Clin Auton Res 27:235-243 |
| George, Lynn; Dunkel, Haley; Hunnicutt, Barbara J et al. (2016) In vivo time-lapse imaging reveals extensive neural crest and endothelial cell interactions during neural crest migration and formation of the dorsal root and sympathetic ganglia. Dev Biol 413:70-85 |
