Date of Award
Doctor of Philosophy (PhD)
Aortic aneurysms are one of the leading causes of death in developed countries. While aneurysms can form anywhere along the arterial tree, thoracic aortic aneurysms and dissections (TAAD), in particular, are associated with a strong genetic component. Currently, mutations in 29 genes have been identified to be causative for TAADs. However, these mutations only account for 25% of known familial TAAD cases. Therefore, identification of more mutations in FTAAD is worth pursuing to expand the panel of screened mutations during clinical genetic testing. Moreover, elucidating the underlying mechanism for TAAD progression from these mutant proteins will be necessary to develop therapeutic agents for these individuals.
Our work revealed a lysyl oxidase (Lox) missense mutation in a family with an autosomal dominant form of TAAD. Introduction of this human mutation into the mouse genome demonstrated that animals homozygous for the mutation had ruptured TAADs at birth, leading to mortality. Conversely, mice heterozygous for the mutation developed into adulthood without aortic dilations, despite fragmented elastic fibers in the ascending aorta. Additionally, we reported that the mutant Lox mRNA and protein were expressed but Lox activity in conditioned media from mutant cells was not detected.
Furthermore, we demonstrated that the mutant LOX is retained in the ER, through direct interactions with calnexin. However, this accumulation did not elicit an ER stress response and the ultimate fate of the retained mutant Lox remains to be determined. We also reported that the animals heterozygous for the mutation require a “second hit” to the cardiovascular system to develop aortic dilations. Together, our work and work by others that identified additional LOX mutations strongly suggest that families with idiopathic TAAD should be screened for missense variants in LOX. Further, future studies will be necessary to determine the catalytic potential for this mutant Lox enzyme; and if it is active, molecular chaperones for the mutant Lox will potentially be able to correct the impaired secretion.
Chair and Committee
Robert P. Mecham
Patrick Y. Jay, Gregory D. Longmore, Jeffrey H. Miner, David M. Ornitz,
Lee, Vivian, "Lysyl Oxidase Mutations in Thoracic Aortic Aneurysm and Dissection" (2018). Arts & Sciences Electronic Theses and Dissertations. 1553.
Available for download on Sunday, May 15, 2118