The autosomal dominant neurodegenerative disorder Huntington's disease-like-2 (HDL2) is caused by a CTG/CAG repeat expansion in exon 2A of the junctophilin 3 (JPH3) gene. A mutant human JPH3 gene containing 116 CTG/CAG repeats in exon 2A is expressed in these mice. Transgene mRNA expression is detected in brain by RT-PCR analysis and is approximately 2 fold greater than endogenous mouse Jph3 expression. Mutant protein levels are not significantly overexpressed. Transgenic mice exhibit progressive motor deficits by 6 months of age. At 3 months of age, no motor deficits are detected. By 12 months of age, transgenic mice have reduced forebrain weight and cortical volume. Ubiquitin-positive nuclear inclusions are detected in transgenic mice as early as 3 months of age in the the cortex and hippocampus. By 12 months of age, nuclear inclusions are detected in a pattern similar to that seen in human patients: upper cortical layers, hippocampus, amygdala, as well as in the cerebral cortex and striatum. Poly(CUG) RNA foci that colocalize with MBNL1 are detected in cortical sections from 6 month old transgenic mice. Mice hemizygous for the transgenic insert are viable, fertile, and normal in size. The Donating Investigator has not attempted to make the strain homozygous.

A mutant human JPH3 gene containing 116 CTG/CAG repeats in exon 2A is expressed in these mice. By 6 months of age they display neurodegeneration accompanied by a progressive motor deficit. Thes mice may have useful applications in the study of the polyglutamine (polyQ) neurodegenerative disease, Huntington's disease-like-2 (HDL2).

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