A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of neurodegene rative storage diseases characterized by progressive psychomotor retardatio n, blindness and premature death. Pathologically, there is accumulation of autofluorescent material in lysosome-derived organelles in a variety of cel l types, but neurons in the central nervous system appear to be selectively affected and undergo progressive death. In this report we show that a nove l form of NCL, congenital ovine NCL, is caused by a deficiency in the lysos omal aspartyl proteinase cathepsin D. A single nucleotide mutation in the c athepsin D gene results in conversion of an active site aspartate to aspara gine, leading to production of an enzymatically inactive but stable protein , This results in severe cerebrocortical atrophy and early death, providing strong evidence for an important role of cathepsin D in neuronal developme nt and/or homeostasis.