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.
Highlights
Congenital heart defects (CHDs) represent the most common birth defect, affecting ~40,000 live births annually in the US [1, 2]
We show that mutations in the gnptab gene, associated with the lysosomal disease mucolipidosis II (MLII), alters the activity and localization of cysteine cathepsins and disrupts heart and AV valve development in zebrafish embryos
Using a TALEN-mediated KO of gnptab, we demonstrate that secretion of cathepsin K increases its activity within the developing heart, and drives local alterations in TGF-β–related signaling
Summary
Congenital heart defects (CHDs) represent the most common birth defect, affecting ~40,000 live births annually in the US [1, 2]. The lysosomal storage disorders (LSDs), genetic diseases that impair either lysosome biogenesis or the catabolic destruction of lysosomal substrates, frequently exhibit cardiac defects [6,7,8,9,10]. One such disorder, mucolipidosis II (MLII), is commonly associated with cardiomyopathy, mitral valve prolapse, and aortic regurgitation [11,12,13]. In MLII mutations in the GNPTAB gene, encoding the catalytic subunits of the GlcNAc-1-phosphotransferase (GNPT) enzyme, impair addition of M6P residues onto N-glycans of lysosomal hydrolases [18, 19]. Without M6P, most soluble hydrolases, including the cathepsin proteases, are hypersecreted from cells
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