Transgenic introduction of human galactosylceramidase into twitcher mouse: Significant phenotype improvement with a minimal expression

Akiko Matsumoto, Marie T. Vanier, Yasushi Oya, Donna Kelly, Brian Popko, David A. Wenger, Kinuko Suzuki, Kunihiko Suzuki

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The twitcher mutant is a naturally occurring mouse model of human Krabbe disease (globoid cell leukodystrophy) caused by a mutation in the gene encoding galactosylceramidase. We have attempted to influence its natural course by introducing human galactosylceramidase gene driven by the mouse myelin basic protein promoter as a transgene. Expression of the transgene was unexpectedly low and could be detected only by RT-PCR. When determined at 35 days, galactosylceramidase activities in the brain and kidney showed increasing activities from the untreated twitchers, twitchers carrying a single transgene, to twitchers carrying a double dose of the transgene. While twitcher mice without the transgene developed the disease early, lost weight and died by 35 ± days, those carrying one transgene developed the disease more slowly, gained weight longer and survived generally to 50 ± days. Those with a double dose of the transgene developed the disease even later, gained weight much longer and survived up to 66 days. Pathology at 35 days suggested corresponding improvements in transgene-carrying twitcher mice. Most importantly, psychosine levels in the brain were reduced to nearly half of those without the transgene. This 'failed' experiment with respect to 'curing' the disease by introduction of the transgene nevertheless provides encouraging evidence to support the hypothesis that a relatively small increment in the enzymatic activity may be sufficient to effect a 'cure' of many lysosomal disorders.

Original languageEnglish (US)
Pages (from-to)142-154
Number of pages13
JournalDevelopmental Brain Dysfunction
Issue number3
StatePublished - May 1 1997


  • Animal model
  • Galactosylceramidase
  • Gene therapy
  • Globoid cell leukodystrophy
  • Psychosine
  • Transgenic treatment
  • Twitcher

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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