Mucopolisaccaridosis II (MPSII), also called Hunter syndrome, is a rare X-linked lysosomal storage disease caused by defects in the activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). IDS is an ubiquitously expressed hydrolase that catalyses the removal of O-linked sulfates from glycosaminoglycans heparan and dermatan sulfate. The disease is multi-systemic and patients exhibit a wide spectrum of clinical features with a distinct early childhood-onset and chronic progressive course. Clinical manifestations include severe skeletal abnormalities, a marked cardiomyopathy and cardiac valve alterations. The current hypothesis suggests that loss of IDS function is tightly associated toa progressive accumulation of partially degraded glycosaminoglycans, which in turn is responsible for the multi-organ failure. However, the cascade of pathogenetic mechanisms is not well understood yet. We recently demonstrated that iduronate-2-sulfatase activity is critical during early vertebrate development (Moro et al.; 2010). We, therefore, hypothesize that major skeletal defects may occur during early development, before the onset of GAG accumulation. To explore this hypothesis we generated a fish model for Hunter syndrome in order to assess early molecular defects occurring as a consequence of IDS loss of function. To shed light on bone impairments we have analyzed several key markers on fish morphants at different developmental stages. Moreover, we carried out IDS loss of function analysis in transgenic reporter lines for major developmental signaling pathways. We found a significant decrease of FGF signaling in morphants, and altered expression of key transcription factors during osteogenesis. Therefore, our preliminary results support the hypothesis that IDS deficiency causes an early dysregulation of the FGF signaling pathway which may be associated with impaired expression of genes involved in bone development.

Loss of lysosomal iduronate sulfatase function perturbs FGF signaling and the expression of downstream key osteogenic factors.

BELLESSO, STEFANIA;SALVALAIO, MARIKA;ZANCAN, ILARIA;COSTA, ROBERTO;MORO, ENRICO
2013

Abstract

Mucopolisaccaridosis II (MPSII), also called Hunter syndrome, is a rare X-linked lysosomal storage disease caused by defects in the activity of the lysosomal enzyme iduronate-2-sulfatase (IDS). IDS is an ubiquitously expressed hydrolase that catalyses the removal of O-linked sulfates from glycosaminoglycans heparan and dermatan sulfate. The disease is multi-systemic and patients exhibit a wide spectrum of clinical features with a distinct early childhood-onset and chronic progressive course. Clinical manifestations include severe skeletal abnormalities, a marked cardiomyopathy and cardiac valve alterations. The current hypothesis suggests that loss of IDS function is tightly associated toa progressive accumulation of partially degraded glycosaminoglycans, which in turn is responsible for the multi-organ failure. However, the cascade of pathogenetic mechanisms is not well understood yet. We recently demonstrated that iduronate-2-sulfatase activity is critical during early vertebrate development (Moro et al.; 2010). We, therefore, hypothesize that major skeletal defects may occur during early development, before the onset of GAG accumulation. To explore this hypothesis we generated a fish model for Hunter syndrome in order to assess early molecular defects occurring as a consequence of IDS loss of function. To shed light on bone impairments we have analyzed several key markers on fish morphants at different developmental stages. Moreover, we carried out IDS loss of function analysis in transgenic reporter lines for major developmental signaling pathways. We found a significant decrease of FGF signaling in morphants, and altered expression of key transcription factors during osteogenesis. Therefore, our preliminary results support the hypothesis that IDS deficiency causes an early dysregulation of the FGF signaling pathway which may be associated with impaired expression of genes involved in bone development.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2838730
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