Looking through the fog


PTEN hamartoma syndrome (PHTS) is a diverse syndrome that develops as the result of mutations in the gene encoding the tumor suppressor PTEN. Cataract formation is common in PHTS patients; however, it is not clear if cataract onset is directly a result of PTEN loss or a secondary effect. Caterina Sellitto and colleagues at Stony Brook University generated a mouse line with lens-specific deletion of Pten to evaluate the contribution of PTEN to cataract development. Lenses from mice lacking PTEN exhibited increased hydrostatic pressure and intracellular sodium concentrations, which led to swelling, cataract, and eye rupture. The authors determined that AKT activation was increased in the lenses of these mice, and pharmacological inhibition of AKT reduced lens pressure. This study demonstrates that PTEN directly regulates lens ion transport via AKT and provides an animal model to investigate PHTS-associated cataract development. The accompanying image shows a WT mouse (top) and a mouse with lens-specific Pten deletion (bottom) at 24 weeks. Cataracts are clearly visible in the mutant animal.  

Published November 25, 2013, by Corinne Williams

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AKT activation promotes PTEN hamartoma tumor syndrome–associated cataract development
Caterina Sellitto, … , Richard T. Mathias, Thomas W. White
Caterina Sellitto, … , Richard T. Mathias, Thomas W. White
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5401-5409. https://doi.org/10.1172/JCI70437.
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Research Article Ophthalmology

AKT activation promotes PTEN hamartoma tumor syndrome–associated cataract development

Abstract

Mutations in the human phosphatase and tensin homolog (PTEN) gene cause PTEN hamartoma tumor syndrome (PHTS), which includes cataract development among its diverse clinical pathologies. Currently, it is not known whether cataract formation in PHTS patients is secondary to other systemic problems, or the result of the loss of a critical function of PTEN within the lens. We generated a mouse line with a lens-specific deletion of Pten (PTEN KO) and identified a regulatory function for PTEN in lens ion transport. Specific loss of PTEN in the lens resulted in cataract. PTEN KO lenses exhibited a progressive age-related increase in intracellular hydrostatic pressure, along with, increased intracellular sodium concentrations, and reduced Na+/K+-ATPase activity. Collectively, these defects lead to lens swelling, opacities and ultimately organ rupture. Activation of AKT was highly elevated in PTEN KO lenses compared to WT mice. Additionally, pharmacological inhibition of AKT restored normal Na+/K+-ATPase activity in primary cultured lens cells and reduced lens pressure in intact lenses from PTEN KO animals. These findings identify a direct role for PTEN in the regulation of lens ion transport through an AKT-dependent modulation of Na+/K+-ATPase activity, and provide a new animal model to investigate cataract development in PHTS patients.

Authors

Caterina Sellitto, Leping Li, Junyuan Gao, Michael L. Robinson, Richard Z. Lin, Richard T. Mathias, Thomas W. White

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