Thesis
A rare C3 glomerulopathy familial case: Insights and models
University of Iowa
Master of Science (MS), University of Iowa
Spring 2022
DOI: 10.17077/etd.006406
Abstract
C3 glomerulopathy (C3G) is a group of rare kidney diseases that manifests from uncontrolled complement activation. The complement system plays a critical role in the innate and adaptive immune system to eliminate pathogens and substances that are no longer required in a host. In C3G, the overactivation of complement leads to deposition or degradation of complement component C3 in the kidney that leads to tissue damage. Within 10 years of diagnosis, 30-50% of patients develop chronic kidney damage that leads to renal failure. Treatments for C3G patients are not optimal and require substantial refinement.
One of the first indicators of complement dysregulation in about two-thirds of patients, is low serum C3 levels. A definitive diagnosis, however, is made through histopathologic examination of the kidney for accumulation of C3. Drivers of disease typically consist of genetic abnormalities and/or autoantibodies that target the C3 and C5 convertases. These drivers contribute to the heterogeneity of the disease but also implicate the clinical outcome and interpretation. Family cases are extremely rare but have been an invaluable source to tackling the many gaps of knowledge that remain in the field. A rare C3G familial case is presented in this thesis to which extensive studies were performed to understand the underlying factors leading to their complement dysregulation and kidney damage. Additionally, a mouse model was created with the goal to recapitulate the disease from this familial case and to further gain insights into the pathogenesis of their disease.
Through genetic testing a novel C3 variant co-segregating with disease was identified in multiple members of the family. With extensive serological studies, we discovered that the underlying factor of ongoing complement activity was due to a resistance of complement regulator CR1. This highlighted an emphasis on the association of this regulator with C3G. The mouse model was able to successfully recapitulate some of the family’s disease characteristics. The regulator resistance remains to be investigated in the mouse model and is an intended future direction to expand our understanding of the regulator association with the pathogenesis of C3G. Our findings suggest that CR1 plays a critical role in the pathogenesis of C3G, and that this regulator might be a target to consider as a therapeutic option.
Details
- Title: Subtitle
- A rare C3 glomerulopathy familial case: Insights and models
- Creators
- Jenifer Valdez
- Contributors
- Richard Smith (Advisor)Daniel Eberl (Advisor)Carla Nester (Committee Member)John Manak (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Integrated Biology
- Date degree season
- Spring 2022
- DOI
- 10.17077/etd.006406
- Publisher
- University of Iowa
- Number of pages
- x, 40 pages
- Copyright
- Copyright 2022 Jenifer Valdez
- Language
- English
- Description illustrations
- Charts, tables
- Description bibliographic
- Includes bibliographical references (pages 35-40).
- Public Abstract (ETD)
C3 glomerulopathy (C3G) is a group of rare kidney diseases that develop from an uncontrolled activation of the complement system. The complement system helps the innate and adaptive immune systems in fighting off infections and getting rid of substances our body no longer requires. In C3G, when complement activation is increased, a complement protein called C3 accumulates in the kidney and causes harm to the tissue. Within 10 years of a patient being diagnosed with C3G, 30-50% of patients will have permanent kidney damage. The current treatments available for C3G patients are imperfect and thus require further improvements.
A common early sign of complement dysregulation is low serum C3 levels, but to confirm diagnosis, the kidney tissue needs to be analyzed for build-up of the C3 protein. Genetic defects and/or antibodies that attack our own tissues and organs contribute to the disease. The complexity of C3G complicates prediction and interpretation of disease symptoms. In this thesis, a family with C3G, which are rare, is described and was thoroughly studied to gain knowledge of how abnormal complement activity is causing injury to the kidney. Our results identified a lack of functional protein important for preventing excessive complement activation. We also created a mouse model to mirror this family’s disease to learn, using techniques not suitable for humans, how this disease is developing and to discover potential treatment options for C3G patients.
- Academic Unit
- Biology
- Record Identifier
- 9984271154802771
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