ZFIN ID: ZDB-PUB-170324-4
Perturbations in cell signaling elicit early cardiac defects in mucopolysaccharidosis type II
Costa, R., Urbani, A., Salvalaio, M., Bellesso, S., Cieri, D., Zancan, I., Filocamo, M., Bonaldo, P., Szabò, I., Tomanin, R., Moro, E.
Date: 2017
Source: Human molecular genetics   26(9): 1643-1655 (Journal)
Registered Authors: Bellesso, Stefania, Costa, Roberto, Moro, Enrico, Salvalaio, Marika, Zancan, Ilaria
Keywords: signal transduction, gag gene, mice, knockout, mucopolysaccharidosis ii, zebrafish, heart
MeSH Terms:
  • Animals
  • Disease Models, Animal
  • Glycoproteins/metabolism*
  • Glycosaminoglycans/metabolism
  • Hedgehog Proteins/metabolism
  • Iduronate Sulfatase
  • Mice
  • Mice, Knockout
  • Mucopolysaccharidosis II/metabolism*
  • Myocardium/cytology
  • Myocardium/metabolism
  • Proteoglycans/metabolism
  • Wnt Signaling Pathway
  • Zebrafish/metabolism
  • Zebrafish Proteins/metabolism
  • beta Catenin
PubMed: 28334757 Full text @ Hum. Mol. Genet.
Morphogens release and activity can be negatively affected by an impaired glycosaminoglycans (GAGs) turnover and proteoglycans assembly in the extracellular matrix, leading to altered tissue morphogenesis. In this work, we show that loss of Iduronate-2-sulfatase (IDS) activity, affecting GAGs catabolism and responsible for a life-threatening valvulopathy in mucopolysaccharidosis type II (MPSII), triggers early Sonic Hedgehog (Shh) and Wnt/β-catenin signaling defects, leading to aberrant heart development and atrioventricular valve formation in a zebrafish model. In addition, we consistently found impaired Shh signaling activity and cardiac electrophysiological abnormalities in IDS knockout mice at postnatal stages before any evident massive GAGs accumulation. These results suggest that IDS activity substantially affect cardiac morphogenesis through impaired Shh signaling and document an unexplored role of the enzyme in the fine-tuning of cell signaling pathways.