BIOCHEMICAL MECHANISMS OF GAMMA SMOOTH MUSCLE ACTIN MUTATIONS UNDERLYING VISCERAL MYOPATHY
| dc.contributor.advisor | Heuckeroth, Robert, O | |
| dc.contributor.advisor | Dominguez, Roberto | |
| dc.contributor.author | Ceron, Rachel, Helen | |
| dc.date.accessioned | 2024-02-01T17:14:48Z | |
| dc.date.available | 2024-02-01T17:14:48Z | |
| dc.date.copyright | 2023 | |
| dc.date.issued | 2023 | |
| dc.date.updated | 2024-02-01T17:14:49Z | |
| dc.description | 2023 | |
| dc.description.abstract | Visceral myopathy (VM) is a rare condition with high morbidity and mortality. Patients with VM experience recurrent abdominal distension, intractable constipation, and often require multiple surgeries and intravenous nutrition to survive. VM results from weakness of smooth muscle lining hollow organs including the bowel. Muscle contraction involves coordinated effort of myosin motors pulling on actin filaments. Smooth muscle cells require a more dynamic actin cytoskeleton than striated muscles and induce actin polymerization in response to contractile stimuli. Causal mutations of VM have been discovered in genes encoding smooth muscle contractile proteins like myosin, actin, and other actin-binding proteins (ABPs) that regulate actin polymerization and actin filament arrangement. The most common cause of VM are heterozygous missense mutations in gamma smooth muscle actin (smooth muscle -actin, ACTG2). It is not known how ACTG2 mutations cause VM, because ACTG2 has never been purified for thorough biochemical characterization. I developed a novel method to produce fully functional native-like human actin proteins so that I could study the biochemical mechanisms of several common ACTG2 mutations. I found that four ACTG2 mutations (R40C, R148C, R178C, and R257C) in different residues spread throughout the protein structure disrupt actin biochemistry in unique ways to cause VM and that their biochemical defects provide insight to differences in clinical disease severity. I hope that this work will guide future studies and aide in the development of novel therapies for VM. | |
| dc.description.degree | Doctor of Philosophy (PhD) | |
| dc.extent | 132 | |
| dc.identifier.uri | https://repository.upenn.edu/handle/20.500.14332/59491 | |
| dc.language.iso | en | |
| dc.subject | Biochemistry, Biophysics, and Structural Biology | |
| dc.subject.other | ACTG2 | |
| dc.subject.other | actin | |
| dc.subject.other | actin mutations | |
| dc.subject.other | visceral myopathy | |
| dc.title | BIOCHEMICAL MECHANISMS OF GAMMA SMOOTH MUSCLE ACTIN MUTATIONS UNDERLYING VISCERAL MYOPATHY | |
| dc.type | Dissertation/Thesis | |
| dspace.entity.type | Publication | |
| upenn.graduate.group | Neuroscience |