BIOCHEMICAL MECHANISMS OF GAMMA SMOOTH MUSCLE ACTIN MUTATIONS UNDERLYING VISCERAL MYOPATHY

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Neuroscience
Discipline
Biochemistry, Biophysics, and Structural Biology
Subject
ACTG2
actin
actin mutations
visceral myopathy
Funder
Grant number
License
Copyright date
2023
Distributor
Related resources
Author
Ceron, Rachel, Helen
Contributor
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.

Advisor
Heuckeroth, Robert, O
Dominguez, Roberto
Date of degree
2023
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation