PUBLICATION
Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure
- Authors
- Li, L.P., Zhong, J., Li, M.H., Sun, Y.C., Niu, Y.J., Wu, C.H., Zhou, J.F., Norton, N., Li, Z.Q., Shi, Y.Y., Xu, X.L., Ding, Y.H.
- ID
- ZDB-PUB-210731-3
- Date
- 2021
- Source
- BioMed Research International 2021: 8569921 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Genetic Predisposition to Disease
- Polymorphism, Single Nucleotide/genetics
- Mutation/genetics
- Myocardium/metabolism
- Zebrafish/genetics*
- Genome-Wide Association Study
- Autophagy
- Doxorubicin/adverse effects*
- Heart Failure/chemically induced*
- Heart Failure/genetics*
- Heart Failure/physiopathology
- Protein Aggregates
- Apoptosis
- Models, Biological
- Myocytes, Cardiac/pathology
- Zebrafish Proteins/genetics*
- DNA Transposable Elements/genetics
- Cardiomyopathies/chemically induced*
- Cardiomyopathies/genetics*
- Risk Factors
- Stress, Physiological
- Muscle, Skeletal/metabolism
- Animals
- PubMed
- 34327238 Full text @ Biomed Res. Int.
Citation
Li, L.P., Zhong, J., Li, M.H., Sun, Y.C., Niu, Y.J., Wu, C.H., Zhou, J.F., Norton, N., Li, Z.Q., Shi, Y.Y., Xu, X.L., Ding, Y.H. (2021) Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure. BioMed Research International. 2021:8569921.
Abstract
Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping