Cathepsin D Deficiency Is Associated with a Human Neurodegenerative Disorder

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 pr...

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Bibliographic Details
Published in:American journal of human genetics 2006-06, Vol.78 (6), p.988-998
Main Authors: Steinfeld, Robert, Reinhardt, Konstanze, Schreiber, Kathrin, Hillebrand, Merle, Kraetzner, Ralph, Brück, Wolfgang, Saftig, Paul, Gärtner, Jutta
Format: Article
Language:English
Subjects:
Adolescent
Amino Acid Sequence
Animals
Biological and medical sciences
Blindness - enzymology
Blindness - genetics
Blindness - pathology
Cathepsin D - analysis
Cathepsin D - genetics
Cathepsin D - metabolism
Disease
DNA polymerase
Enzymes
Female
Fibroblasts - enzymology
General aspects. Genetic counseling
Genes
Heterozygote
Humans
Male
Medical genetics
Medical sciences
Mice
Molecular Sequence Data
Mutation
Mutation, Missense
Neurodegenerative Diseases - enzymology
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - pathology
Neurological disorders
Protein Conformation
Psychomotor Disorders - enzymology
Psychomotor Disorders - genetics
Psychomotor Disorders - pathology
Schwann Cells - enzymology
Schwann Cells - ultrastructure
Transfection
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Summary: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.
ISSN:0002-9297
1537-6605
DOI:10.1086/504159