Twitcher mice with only a single active galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements

Takanori Ezoe, Marie T. Vanier, Yasushi Oya, Brian Popko, Jun Tohyama, Junko Matsuda, Kinuko Suzuki, Kunihiko Suzuki

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cross-breeding of mouse mutants, each defective in either synthesis (CGT knockout) or degradation (twitcher) of galactosylceramide, generates hybrids with a genotype of galc(-/-), cgt(+/-), in addition to doubly deficient mice. They are ideally suited to test the potential usefulness of limiting synthesis of the substrate as a treatment of genetic disorders due to degradative enzyme defects. The rate of accretion of galactosylceramide in the brain of CGT knockout carrier mice (cgt(+/-)) is approximately two-thirds of the normal, suggesting a gene-level compensation for the reduced gene dosage. Phenotype of twitcher mice with a single dose of normal cgt gene was indeed milder with statistical significance, albeit only slightly. Compared among 10 paired littermates, the difference in the life span was 7 ± 3.9 days (S.D.) and the difference in the maximum attained body weight was 1.9 ± 1.2 g (S.D.). Neuropathologists were able to distinguish blindly galc(-/-), cgt(+/-) mice from galc(-/-), cgt(+/+) mice. The brain psychosine level in galc(-/-), cgt(+/-) mice was also approximately two-thirds of the galc(-/-), cgt(+/+) mice. These observations indicate that reduction of galactosylceramide synthesis to two-thirds of the normal level results in minor but clearly detectable phenotypic improvements. Because of the detrimental consequences of drastic reduction in galactosylceramide synthesis that may be required for pragmatically meaningful improvements, this approach by itself is unlikely to be useful as the sole treatment but may be helpful as a supplement to other therapies.

Original languageEnglish (US)
Pages (from-to)179-187
Number of pages9
JournalJournal of Neuroscience Research
Volume59
Issue number2
DOIs
StatePublished - Jan 15 2000

Keywords

  • Genetic reduction of substrate synthesis
  • Globoid cell leukodystrophy
  • Krabbe disease
  • Lysosomal disease
  • Treatment

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Twitcher mice with only a single active galactosylceramide synthase gene exhibit clearly detectable but therapeutically minor phenotypic improvements'. Together they form a unique fingerprint.

Cite this