JPH3 – Huntington disease-like 2

Junctophilin 3 (JPH3) is implicated in Huntington disease-like 2 (HDL2), a progressive autosomal dominant neurodegenerative syndrome clinically resembling Huntington disease but with an average onset ~5 years later. HDL2 results from CAG/CTG repeat expansions in the neuronal JPH3 gene, and all affected individuals reported to date have African ancestry.

In a cohort of South African patients referred for Huntington disease testing, 20 of 130 black patients (15%) harbored pathogenic JPH3 expansions, whereas none of 171 white patients did (PMID:26079385). Affected individuals exhibit abnormal movements, cognitive decline, psychiatric symptoms, and a later age of onset compared to classical HD.

Haplotype analysis across 31 families provides strong segregation and founder‐mutation evidence for a single African origin of the JPH3 expansion (PMID:26079385). This supports autosomal dominant transmission in multiple unrelated kindreds.

Functional studies in JPH3 knockout mice demonstrate impaired balance and motor coordination, mirroring key HDL2 motor manifestations and indicating that JP-3 is essential for neuronal junctional membrane integrity (PMID:11906164). These concordant in vivo data reinforce the pathogenic role of JPH3 disruption in HDL2.

A recent comprehensive review of junctophilin proteins highlights that trinucleotide expansions in JPH3 cause HDL2 and underscores the critical structural role of JP-3 in excitable cells, alongside isoform-specific disease associations (PMID:35001666).

Together, robust genetic and experimental evidence supports a Strong gene–disease association for JPH3 and HDL2, with reproducible segregation, multiple unrelated probands, and functional concordance. Routine testing for JPH3 expansions is clinically indicated in individuals of African ancestry presenting with an HD phenotype.

References

• American Journal of Medical Genetics Part B • 2015 • Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. PMID:26079385
• Biochemical and Biophysical Research Communications • 2002 • Motor discoordination in mutant mice lacking junctophilin type 3. PMID:11906164
• Physiological Reviews • 2022 • The role of junctophilin proteins in cellular function. PMID:35001666

Evidence Based Scoring (AI generated)