The spontaneous mutant toppler is an allele of Lass1, a neuronally expressed ceramide synthase. Homozygotes exhibit progressive ataxia, Purkinje cell loss, and an accumulation of lipofuscin and may be useful for studies examining the role of lipid biosynthesis in neurodegenerative diseases.
Wendy Macklin, University of Colorado
Lass1 (LAG1 homolog, ceramide synthase 1) is a neuronally expressed enzyme that encodes (dihydro) ceramide synthase (CerS1). Ceramide functions as as a basic structural component of sphingolipids. Alterations in sphingolipid homeostasis are implicated in neurodegenerative disease. Toppler was identified as a C to A missense point mutation in exon 5 of the Lass1 gene. Mice homozygous for the spontaneous toppler mutation are viable and fertile. Beginning at 12-14 days, pups exhibit mild tremors when agitated. Tremors progress to ataxia and loss of balance. Mutant mice adopt a unique tripod stance using the hind limbs and tail as a base, while leaning against cage walls. Homozygotes exhibit reduced body size, a 25-50% decrease in cerebellum size, abnormal accumulation of lipofuscin, loss of Bergmann glia, and, between P21 and P30, a major loss of Purkinje cells. This mutant strain may be useful for studies examining the role of lipid biosynthesis in neurodegenerative diseases.
The toppler (top) mutation arose spontaneously in a colony of FVB/N mice carrying a transgene expressing the neomycin resistance marker (pSVtkneo) in the laboratory of Dr. Wendy Macklin at the Cleveland Clinic Foundation in 2003. The mutation was identified in 4 female mice from a litter of 11 that exhibited ataxia and abnormal posturing. Subsequent outcrossing to (C3H x C57LB/6J)F1 and selection against the transgene indicated that the mutation was heritable and independent of the transgene. Mice then were transferred to the laboratory of Dr. Susan Ackerman at The Jackson Laboratory. Toppler was identified as a C to A missense point mutation in exon 5 of the Lass1 gene. The mutation alters the corresponding amino acid from aspartic acid to alanine at position 266. Dr. Macklin donated this strain to The Jackson Laboratory Repository in 2012. Upon arrival, mice were bred to FVB/NJ for at least 1 generation to establish the colony.
|Gene Symbol and Name||Cers1, ceramide synthase 1|
|Strain of Origin||FVB/N-Tg(TK-neo)#Doe|
|Molecular Note||A spontaneous C to A substitution results in an alanine to aspartic acid substitution at position 266 (p.A266D).|
While maintaining a live colony, these mice are bred as heterozygotes.
When using the FVB/N-Cers1to/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #019483 in your Materials and Methods section.