HDL2_JPH3
- Gene
- JPH3
- Disease
- HDL2
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 15
- Publications Reviewed
- 5
- Publication Span
- 23.58 years
- Last Updated
- 06/04/2025
- Curator(s)
- Laurel Hiatt, Harriet Dashnow
Description
HDL2 is an autosomal dominant Huntington disease phenocopy caused by a CAG/CTG repeat expansion in alternatively spliced exon 2A of JPH3. Human evidence includes published genetically confirmed HDL2 cases, an inverse relationship between repeat length and age at onset, and shared African-origin founder haplotypes in multiple populations. Experimental evidence includes BAC-HDL2 mouse models with motor and neurodegenerative phenotypes, CUG RNA foci and polyQ nuclear inclusions, gene-level Drosophila junctophilin models modifying neuronal/polyQ phenotypes, and localization of the repeat to alternatively spliced JPH3 exon 2A.
Genetic evidence
Total: 9
| Singular Evidence | Probands | PMID:28339400 | 6 | Systematic review identified 69 published genetically confirmed HDL2 cases through 2016; clinical features overlapped Huntington disease, including chorea, dementia, parkinsonism and psychiatric manifestations. |
| Collective Evidence | Allele | PMID:28339400 | 2 | Across published HDL2 cases, expanded JPH3 repeat length showed a strong inverse correlation with age at onset (Pearson r = -0.76; p < 0.0001). |
| Collective Evidence | Segregation | PMID:40187026 | 1 | Twelve JPH3 expansion carriers from five Mexican families shared a 746-kb African-origin haplotype within a 1.1-Mb African segment flanking JPH3, supporting a founder mutation; formal LOD-based segregation was not reported. |
Experimental evidence
Total: 6
| Models | Non-human model organism | PMID:21555070 | 2 | BAC-HDL2 mice carrying expanded CTG/CAG repeats in JPH3 exon 2A showed age-dependent motor deficits, forebrain/cortical atrophy, CUG RNA foci, ubiquitin/polyQ nuclear inclusions and antisense HDL2-CAG/polyQ pathogenesis. |
| Models | Non-human model organism | PMID:29208631 | 2 | Gene-level, not HDL2 repeat-locus-specific: altered Drosophila junctophilin (jp) expression caused muscular, cardiac and neuronal phenotypes and modified Htt-Ex1-pQ93/SCA3-Q89 polyQ retinal degeneration. |
| Function | Regulatory impact | PMID:11694876 | 2 | The HDL2 CTG repeat was localized 760 nt 3' of JPH3 exon 1 within alternatively spliced exon 2A; RT-PCR of normal brain mRNA confirmed three exon 1-exon 2A splice variants using different acceptor sites. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.