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Author Notes:

Correspondence: Heather Flanagan-Steet, Greenwood Genetic Center, J.C. Self Research Institute, 113 Gregor Mendel Circle, Greenwood, South Carolina 29646, USA. Phone: 864.388.1806; Email: heatherfs@ggc.org

Author contributions: PL, TM, and CJC performed experiments and interpreted data. TCL provided the DNA constructs containing TALEN sequences used to generate gnptab-KO lines. RAS assisted with data interpretation and manuscript preparation. HFS designed and performed experiments, interpreted data, and wrote the manuscript.

We would like to thank Brian Kwan for his early contributions and help generating the gnptab-KO line. We would also like to thank Matthew Bogyo (Stanford University) for contributing the BMV109 and BMV157 probes used in this study.

We would like to thank Koichi Kawakami and Yoshiko Takahashi (National Institute of Genetics, Japan) for providing the TOL2 transgenesis constructs (MTA K2019-055) (68). Additionally, we are grateful to Andrei Alexandrov (Clemson Center for Human Genetics) for his expert assistance with FAC sorting of zebrafish cells.

We would also like to acknowledge that much of the zebrafish work related to this study was performed on animals raised in the Hazel and Bill Allin Aquaculture Facility housed at the Greenwood Genetic Center. We thank the staff of the facility for their excellent animal care and husbandry.

Subjects:

Research Funding:

This work was supported by an R01 to RS from the NIHGMS GM086524, grants to HFS from the National MPS Society and the ISMRD, as well as a grant to RS by the Yash Ghandi Foundation.

Additionally, we have received funds from the National MPS Society and ISMRD.

Keywords:

  • Cell Biology
  • Development
  • Cardiovascular disease
  • Lysosomes
  • Proteases

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

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Journal Title:

JCI insight

Volume:

Volume 5, Number 20

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Type of Work:

Article | Final Publisher PDF

Abstract:

Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab-deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β–related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.

Copyright information:

© 2020, Lu et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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