A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis

Tomoyuki Awano, Martin L. Katz, Dennis P. O'Brien, Jeremy F. Taylor, Jason Evans, Shahnawaz Khan, Istvan Sohar, Peter Lobel, Gary S. Johnson

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


We obtained DNA, brains, and eyes from American Bulldogs with neurodegeneration due to neuronal ceroid lipofuscinosis (NCL). The diagnosis of NCL was confirmed by detection of autofluorescent cytoplasmic inclusions within neurons throughout the brains, in retinal ganglion cells, and along outer limiting membranes of the retinas. Electron microscopy revealed that the inclusions had coarsely granular matrices surrounding well-delineated spherical structures and that the inclusions near the retinal outer limiting membranes were within photoreceptor cells, mostly cones. Affected American Bulldogs were homozygous for the A allele of a G to A transition in the cathepsin D gene (CTSD), which predicts the conversion of methionine-199 to an isoleucine. Only the G allele was detected in DNA samples from 131 randomly selected dogs representing 108 breeds other than American Bulldog; however, the A allele had a frequency of 0.28 among 123 genotyped American Bulldogs. Transmission analysis in a 99 dog pedigree of American Bulldogs indicated a probability of less than 10-7 that alleles from any mutation unlinked to CTSD would be concordant with the pedigree and phenotypes of the dogs. Brain samples from affected dogs had 36% of the cathepsin D-specific enzymatic activity found in control dog brains; whereas, specific enzymatic activities of 15 other lysosomal enzymes were unchanged or increased. Compared to previously described NCLs in mice and sheep that completely lack cathepsin D activity, the clinical course of NCL in the American Bulldogs was less severe and more closely resembled that of many human NCLs.

Original languageEnglish (US)
Pages (from-to)341-348
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - Apr 2006

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


  • CTSD
  • Canine
  • Cathepsin D
  • Missense mutation
  • Neuronal ceroid lipofuscinosis


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