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
  • Stress, Physiological
  • Myocytes, Cardiac/pathology
  • Cardiomyopathies/chemically induced*
  • Cardiomyopathies/genetics*
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Protein Aggregates
  • DNA Transposable Elements/genetics
  • Myocardium/metabolism
  • Polymorphism, Single Nucleotide/genetics
  • Mutation/genetics
  • Muscle, Skeletal/metabolism
  • Doxorubicin/adverse effects*
  • Risk Factors
  • Animals
  • Heart Failure/chemically induced*
  • Heart Failure/genetics*
  • Heart Failure/physiopathology
  • Zebrafish/genetics*
  • Autophagy
  • Models, Biological
  • Zebrafish Proteins/genetics*
  • Apoptosis
(all 23)
PubMed
34327238 Full text @ Biomed Res. Int.
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
Figures
Figure Gallery (4 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
EGFPxu062Tgstandard conditionsAdultIFL
mRFP1map7d1bmn0239Gt/mn0239Gtstandard conditionsAdultIFL
mRFP1map7d1bmn0239Gt/mn0239Gtstandard conditionsProtruding-mouthIFL
mRFP1map7d1bmn0239Gt/mn0239Gtstandard conditionsProtruding-mouthIFL
1 - 4 of 4
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Phenotype
Fish Conditions Stage Phenotype Figure
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
map7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinAdult
1 - 7 of 7
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mn0239GtTransgenic Insertion
xu062TgTransgenic Insertion
    1 - 2 of 2
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    cardiomyopathymap7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinTAS
    congestive heart failuremap7d1bmn0239Gt/mn0239Gtchemical treatment by injection: doxorubicinTAS
    1 - 2 of 2
    Show
    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    map7d1bmn0239Gt/mn0239Gt
    xu062Tg
    1 - 2 of 2
    Show
    Antibodies
    Orthology
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    GFPEFGGFP
    mRFP1EFGmRFP1
    1 - 3 of 3
    Show
    Mapping
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    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.