These Cln3 knock-out mice exhibit retinal degeneration, neurodegeneration, and reduced survival.
Dr. Marcy E MacDonald, Massachusetts General Hospital
Mice that are homozygous for the targeted mutation are viable and fertile, but have reduced survival, which drops to 80% by 12 months of age. Northern blot and RT PCR analyses of kidney, liver and brain tissue from homozygotes detect mutant mRNA. Truncated polypeptide and non-truncated alternatively spliced gene products are present. This 1.02kb deletion mutation replicates the most common mutation (>80%) found in Juvenile-onset neuronal ceroid lipofuscinosis (JNCL) patients. Autofluorescent lysosomal material containing immunoreactive ATPase subunit c are found in all tissues. Neuron and hepatocyte membrane deposits begin to accumulate as early as E19.5. Electron microscopic analysis reveals inclusions characteristic of JNCL tissue. Hypopigmented homozygotes exhibit retinal degeneration beginning at 10 months of age. Gliosis in the CNS and abnormal clasping behavior and gait traces indicate neurodegeneration. Onset and severity of disease phenotype is variable, which might be due to the mixed genetic background. Heterozygous mice do not display the phenotype. This mutant mouse strain may be useful in studies of Juvenile-onset neuronal ceroid lipofuscinosis (JNCL), Batten or Spielmeyer-Vogt disease.
A targeting vector containing a loxP site flanked neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter was used to disrupt exons 7 and 8 and adjacent non-coding sequence of the targeted gene. The construct was electroporated into 129-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts.
|Allele Name||targeted mutation 1.1, Marcy MacDonald|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Cln3, ceroid lipofuscinosis, neuronal 3, juvenile (Batten, Spielmeyer-Vogt disease)|
|Strain of Origin||(129X1/SvJ x 129S1/Sv)F1-Kitl+|
|Molecular Note||A floxed neo cassette that had replaced exons 7 and 8 was excised from Cln3tm1Mem via in vivo cre mediated recombination in the germline. Expression analyses showed the presence of various aberrantly splice transcripts. Translation of a cDNA derived from RT-PCR analysis produced a protein containing the amino and carboxyl terminals as well as a novel mid-section. BLASTN revealed homology with a protein isolated from a patient with the juvenile-onset form of neuronal ceroid lipofuscinosis (JNCL).|
|Mutations Made By|| |
Dr. Marcy MacDonald, Massachusetts General Hospital
The resulting line was then bred a CMV-cre transgenic strain to delete the neo cassette from the targeted allele. The strain is maintained on an outbred 129SvEv, CD1 background. When held in a live colony, it is maintained as a hemizygote.
When using the Cln3deltaex7/8 mouse strain in a publication, please cite the originating article(s) and include JAX stock #004685 in your Materials and Methods section.
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