Inherited diseases caused by mutations in cathepsin protease genes

FEBS J. 2017 May;284(10):1437-1454. doi: 10.1111/febs.13980. Epub 2017 Jan 12.


Lysosomal cathepsins are proteolytic enzymes increasingly recognized as prognostic markers and potential therapeutic targets in a variety of diseases. In those conditions, the cathepsins are mostly overexpressed, thereby driving the respective pathogenic processes. Although less known, there are also diseases with a genetic deficiency of cathepsins. In fact, nowadays 6 of the 15 human proteases called 'cathepsins' have been linked to inherited syndromes. However, only three of these syndromes are typical lysosomal storage diseases, while the others are apparently caused by defective cleavage of specific protein substrates. Here, we will provide an introduction on lysosomal cathepsins, followed by a brief description of the clinical symptoms of the various genetic diseases. For each disease, we focus on the known mutations of which many have been only recently identified by modern genome sequencing approaches. We further discuss the effect of the respective mutation on protease structure and activity, the resulting pathogenesis, and possible therapeutic strategies.

Keywords: Papillon-Lefèvre syndrome; galactosialidosis; myopia; neuronal ceroid lipofuscinosis; pycnodysostosis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsins / genetics
  • Cathepsins / metabolism*
  • Humans
  • Mutation / genetics
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Papillon-Lefevre Disease / genetics
  • Papillon-Lefevre Disease / metabolism
  • Pycnodysostosis / genetics
  • Pycnodysostosis / metabolism


  • Cathepsins