Human Molecular Genetics Advance Access published online on August 18, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh264
© 2004 by Oxford University Press
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1 Pädiatrie II, Zentrum Kinderheilkunde und Jugendmedizin, Universitätsklinikum Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
* To whom correspondence should be addressed. E-mail: rsteinfeld{at}med.uni-goettingen.de.
Classical late infantile neuronal ceroid lipofuscinosis is an autosomal recessive disease caused by mutations in the CLN2 gene resulting in functional defects of the gene product tripeptidyl-peptidase I. This disease is associated with a progressive neurodegenerative course beginning at the age of two years with developmental stagnation, finally leading to a complete loss of motor function, vision and speech by the age of ten years. We analyzed the functional consequences of the mutations R127Q, R208X, N286S, I287N, T353P, and Q422H, which were previously identified in patients with late infantile ceroid lipofuscinosis, with regard to enzymatic activity, stability, posttranslational processing, and intracellular localisation of tripeptidyl-peptidase I. We could not detect any translational product for the mutant R208X. We found that four missense mutations, N286S, I287N, T353P, and Q422H, which are located in conserved protein regions of tripeptidyl-peptidase I, decreased dramatically enzymatic activity, blocked processing to mature size peptidase, and led to protein retention in the endoplasmatic reticulum and rapid degradation in non-lysosomal compartments. We conclude that these amino acid substitutions induce major misfolding of the precursor peptidase and hence prevent posttranslational processing and lysosomal targeting of tripeptidyl-peptidase I. In contrast, the amino acid substitution R127Q within a non-conserved protein region did not significantly affect enzymatic activity, stability, processing and lysosomal targeting of tripetidyl-peptidase I. Thus, our functional analyses of CLN2 mutations reveal novel insight into the molecular defect underlying dysfunction of tripeptidyl-peptidase I.
Article
Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes
2 Department of Pediatrics, University Hospital Eppendorf, Hamburg, Germany
3 Centre of Molecular Neurobiology (ZMNH), University of Hamburg, Hamburg, Germany
4 Department of Pediatrics and Pediatric Neurology, University of Göttingen, Göttingen, Germany
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