JPH3 Gene: Function, Mutations, and Associated Diseases | Biomedical Resource

The JPH3 gene encodes junctophilin-3, a protein that plays a crucial role in the formation of junctional membrane complexes between the plasma membrane and the endoplasmic/sarcoplasmic reticulum. These complexes are essential for excitation-contraction coupling in muscle cells and for calcium signaling in neurons. JPH3 is primarily expressed in the brain, particularly in the striatum and cortex, and is involved in maintaining intracellular calcium homeostasis. Mutations in JPH3, specifically an expanded CAG/CTG repeat in the 5' region, cause Huntington's disease-like 2 (HDL2), a rare autosomal dominant neurodegenerative disorder with clinical features similar to Huntington's disease.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Calcium signaling pathway (Reactome: R-HSA-4086398)

• Excitation-contraction coupling (Reactome: R-HSA-5576891)

• Neurodegeneration pathways (KEGG: hsa05016)

Junctophilin-3 is a 748-amino acid protein with a molecular weight of approximately 85 kDa. It contains a C-terminal transmembrane domain that anchors it to the endoplasmic/sarcoplasmic reticulum membrane, and an N-terminal domain that interacts with the plasma membrane. The protein forms junctional membrane complexes that are critical for the close apposition of the ER/SR and the plasma membrane, facilitating calcium release and signaling. In neurons, JPH3 is involved in calcium homeostasis, synaptic plasticity, and neuronal survival. Mutations in JPH3, particularly the CAG/CTG repeat expansion, lead to a toxic RNA that disrupts RNA processing and contributes to neurodegeneration in HDL2.