title: Delayed clinical and pathological signs in twitcher (globoid cell leukodystrophy) mice on a C57BL/6 x CAST/Ei background.
abstract: Modifier genes may account for the phenotypic variability observed in the late-onset forms of globoid cell leukodystrophy (GCL) in humans. In order to begin a search for modifier genes, the effect of genetic background on the clinical and pathological manifestations of GCL was investigated in twitcher mice. Twitcher mice on a C57BL/6 x CAST/Ei background had an increased life span (61.4 +/- 2.5 vs 37.0 +/- 0.6 days), a delayed onset of tremor (24 vs 21 days), and a delayed decline in walking ability compared to C57BL/6 twitcher mice. Pathologically, C57BL/6 x CAST/Ei twitcher mice had fewer lectin-positive globoid cells, less gliosis, and a greater preservation of myelin compared to C57BL/6 twitcher mice under moribund conditions. Similar concentrations of psychosine, the toxic species that accumulates in GCL, were measured by tandem mass spectrometry between moribund C57BL/6 twitcher mice (286.5 pmol/mg protein), 40-day C57BL/6 x CAST/Ei twitcher mice (276.5 pmol/mg), and moribund C57BL/6 x CAST/Ei twitcher mice (247.0 pmol/mg), suggesting that the milder phenotype in CAST/Ei x C57BL/6 twitcher mice did not correlate with less psychosine. In summary, the introduction of modifier genes from the wild, inbred CAST/Ei strain had a phenotypic effect resulting in a significantly slower disease course.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kacsas City, 66160, USA.
authors.forename: Sangita
authors.initials: S
authors.lastname: Biswas
authors.forename: Homigol
authors.initials: H
authors.lastname: Biesiada
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.forename: Steven M
authors.initials: SM
authors.lastname: LeVine
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D011609:Psychosine / Q000096:biosynthesis
chemical_list: D011609:Psychosine