Key result
While human TRIM21 showed 68% homology to T. cruzi Ag 36, mouse and rat TRIM21 showed 0% homology despite developing Chronic Chagas Cardiomyopathy, indicating the homology is likely not causative.
Why the study?
To test the hypothesis that T. cruzi Ag 36 represses Ro52 (TRIM21) to cause autoimmunity in Chronic Chagas Cardiomyopathy, by assessing gene homology across mammalian TRIM genes.
The lack of homology between T. cruzi Ag 36 and TRIM21 in mice and rats, which can develop Chronic Chagas Cardiomyopathy, suggests this gene homology is not the causative mechanism for the disease's autoimmunity.
Answers are grounded in this paper and cite their sources.
Questions TRIM21 homology as driver of Chagas autoimmunity; hypothesis-generating and leaves mechanism open for human studies.
Background We previously reported that a Human Ro52 gene sequence (TRIM21) produced a significant stretch of protein sequence homologous to T. cruzi Antigen 36 (Ag 36) protein sequence, when Ag 36 was translated in the second reading frame. Comparison of their respective DNA sequences demonstrated a 114 nucleotide region of both genes having ~ 70 percent partial homology. After Ro52 was shown to be an E3 Ubiquitin dependent Type I ligase for transcription factors for Interferon genes, we proposed that the Ag 36 gene, which contains a repetitive motif within it, may function to repress Ro52 in the human heart through RNA interference, or other unknown mechanism, giving rise to autoimmunity found in Chronic Chagas Cardiomyopathy (CCC). Results To test that hypothesis, we compared various mammalian TRIM genes to the T. cruzi Ag 36 DNA sequence using the Needleman-Wunsch algorithm in the http:\.eu bioinformatics tool base. In addition to human and chimpanzee, TRIM21 comparable gene regions from canine, shrew, ferret, bat, feline, and armadillo, and aardvark showed homology to the gene for Ag 36 ranging from 68 to 30 percent. However, mouse and eight other mammalian species showed no significant homology. Since mice have been shown to have severe cardiac cardiomyopathy after infection, but their TRIM21 was not homologous to Ag 36 in this study, we conclude that the gene homology has no causative link to CCC. Conclusions In addition to human TRIM21, eight mammalian species showed partial gene homology to T. cruzi Ag 36, and some of these have been demonstrated to have CCC. However, rats and mice TRIM21 showed no partial homology to Ag 36. Since these species have been demonstrated to have CCC, the partial gene homology between Ag36 and TRIM 21 may not be causative or associated with CCC, as was originally hypothesized.
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Winkler et al. (2021) studied Chronic Chagas Cardiomyopathy. Needleman-Wunsch alignment of TRIM21 genes vs. T. cruzi Ag 36 was evaluated on Percent homology in the TRIM21 nucleotide 856 to 916 range. While human TRIM21 showed 68% homology to T. cruzi Ag 36, mouse and rat TRIM21 showed 0% homology despite developing Chronic Chagas Cardiomyopathy, indicating the homology is likely not causative.
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