title: Cathepsin D deficiency is associated with a human neurodegenerative disorder.
abstract: Cathepsin D is a ubiquitously expressed lysosomal protease that is involved in proteolytic degradation, cell invasion, and apoptosis. In mice and sheep, cathepsin D deficiency is known to cause a fatal neurodegenerative disease. Here, we report a novel disorder in a child with early blindness and progressive psychomotor disability. Two missense mutations in the CTSD gene, F229I and W383C, were identified and were found to cause markedly reduced proteolytic activity and a diminished amount of cathepsin D in patient fibroblasts. Expression of cathepsin D mutants in cathepsin D(-/-) mouse fibroblasts revealed disturbed posttranslational processing and intracellular targeting for W383C and diminished maximal enzyme velocity for F229I. The structural effects of cathepsin D mutants were estimated by computer modeling, which suggested larger structural alterations for W383C than for F229I. Our studies broaden the group of human neurodegenerative disorders and add new insight into the cellular functions of human cathepsin D.
authors: Department of Pediatrics and Pediatric Neurology, University of Gottingen, Gottingen, Germany. rsteinfeld@med.uni-goettingen.de
authors: Robert
authors: R
authors: Steinfeld
authors: Konstanze
authors: K
authors: Reinhardt
authors: Kathrin
authors: K
authors: Schreiber
authors: Merle
authors: M
authors: Hillebrand
authors: Ralph
authors: R
authors: Kraetzner
authors: Wolfgang
authors: W
authors: Bruck
authors: Paul
authors: P
authors: Saftig
authors: Jutta
authors: J
authors: Gartner