{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T10:32:54Z","timestamp":1791023574544,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,2,24]],"date-time":"2012-02-24T00:00:00Z","timestamp":1330041600000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2012,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective:<\/jats:title><jats:p>Huntington disease\u2010like 2 (HDL2) is a progressive, late onset autosomal dominant neurodegenerative disorder, with remarkable similarities to Huntington disease (HD). HDL2 is caused by a CTG\/CAG repeat expansion. In the CTG orientation, the repeat is located within the alternatively spliced exon 2A of <jats:italic>junctophilin\u20103<\/jats:italic> (<jats:italic>JPH3<\/jats:italic>), potentially encoding polyleucine and polyalanine, whereas on the strand antisense to <jats:italic>JPH3<\/jats:italic>, the repeat is in frame to encode polyglutamine. The <jats:italic>JPH3<\/jats:italic> protein product serves to stabilize junctional membrane complexes and regulate neuronal calcium flux. We have previously demonstrated the potential pathogenic properties of <jats:italic>JPH3<\/jats:italic> transcripts containing expanded CUG repeats. The aim of this study was to test the possibility that loss of <jats:italic>JPH3<\/jats:italic> expression or expanded amino acid tracts also contribute to HDL2 pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Transcripts from the HDL2 locus, and their protein products, were examined in HDL2, HD, and control frontal cortex. The effect of loss of <jats:italic>Jph3<\/jats:italic> was examined in mice with partial or complete loss of <jats:italic>Jph3<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Bidirectional transcription occurs at the HDL2 locus, although expression of antisense transcripts with expanded CAG repeats is limited. Protein products with expanded amino acid tracts were not detected in HDL2 brain. However, <jats:italic>JPH3<\/jats:italic> transcripts and full\u2010length <jats:italic>JPH3<\/jats:italic> protein are decreased in HDL2 brain, and <jats:italic>Jph3<\/jats:italic> hemizygous and null mice exhibit abnormal motor function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation:<\/jats:title><jats:p>Our results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of <jats:italic>JPH3<\/jats:italic> RNA and a toxic loss of <jats:italic>JPH3<\/jats:italic> expression. 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