A novel role of the Batten disease gene CLN3: association with BMP synthesis.

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) results from a deficiency of CLN3, a protein recently identified within detergent-resistant membranes (DRMs). To study the function of CLN3 within these domains we isolated DRMs from control and JNCL-brain and noted that JNCL-derived DRMs are less buoyant than control. Analysis of DRM phospholipids derived from JNCL-brain revealed a reduction of bis(monoacylglycerol)phosphate. Metabolic labeling of JNCL-fibroblasts demonstrated a reduction in the synthesis of bis(monoacylglycerol)phosphate which was restored following complementation with wild-type-CLN3, substantiating our initial observation in brain. Metabolic labeling of cell lines overexpressing wild-type-CLN3 resulted in increased bis(monoacylglycerol)phosphate synthesis, while overexpression of mutant CLN3-L170P decreased bis(monoacylglycerol)phosphate synthesis. These data illustrate a new finding, a strong correlation between CLN3 protein expression and synthesis of bis(monoacylglycerol)phosphate.