Probing cataractogenesis associated with mevalonic aciduria

Abstract

PURPOSE. Mevalonic aciduria in humans results from a genetic deficiency of mevalonate kinase and is characterized by very high plasma mevalonic acid levels, developmental malformations and cataracts. This study tested the possibility that the cataracts could result from direct toxicity of the accumulated mevalonate. METHODS. Young rat lenses were cultured for up to 4 days in medium TC199 containing 1 to 5 mM mevalonic acid. Changes in the water, sodium and potassium content of the lens were followed; electrolytes were measured by atomic absorption spectroscopy. The identities of proteins leaked from the lens were determined by sodium dodecylsulfate polyacrylamide electrophoresis and isoelectric focusing. Changes in cation flux were measured by 86 Rb uptake. Lens concentrations of mevalonic acid were measured from uptake of 3 H-mevalonolactone. RESULTS. Culture of young rat lenses with 3 to 5 mM mevalonic acid produced lens opacification and nuclear cataracts starting within 1 to 2 days of culture. Mevalonic acid did not concentrate in the lens. Treated lenses accumulated water and sodium and lost potassium and soluble gamma crystallin proteins. These changes were preceded by a loss of the lens's capacity to concentrate 86 Rb, a potassium analogue. The loss of 86 Rb uptake might have been due to a slow poisoning of the cation pump, direct effects on membrane integrity or both. CONCLUSIONS. The results show that chronic exposure of the lens to mevalonic acid can induce cataracts, which appear caused by a progressive increase in the permeability of lens cell membranes. The cataracts associated with mevalonic aciduria could be due to toxicity from mevalonic acid.