This report describes Huntington disease-like 2 (HDL2); HDL2 exhibits autosomal recessive inheritance. The human gene associated with this disease JPH3, one of four junctophilin genes in human. Junctophilins are components of junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum: JPH3 is brain-specific.
One isoform of the human Hsap\JPH3 contains an exon with variable numbers of GCT triplets; this results in a poly-alanine repeat of variable length. It is hypothesized that the pathogenicity of HDL2 is not due to the Hsap\JPH3 transcript and protein, but to an anti-sense transcript that produces a protein carrying poly-glutamine (polyQ) repeats. Multiple constructs driving transcription of the antisense product have been introduced into flies; these are indicated in FlyBase using allele symbols Hsap\JPH3[HDL2*]. Constructs carrying an expanded polyQ-generating repeat region have been assessed; when expressed in neurons, large nuclear aggregates are observed, with only smaller puncta observed in the cytoplasm. This is in contrast to observations for a Drosophila model of Huntington disease (FBhh0000003), in which polyQ aggregates localize exclusively to the cytoplasm.
The single junctophilin gene in Drosophila, jp, has been used to model other diseases caused by this gene family; see the report for 'neuromuscular disease, JPH-related' (FBhh0000819).
[updated Feb. 2021 by FlyBase; FBrf0222196]
[HUNTINGTON DISEASE-LIKE 2; HDL2](https://omim.org/entry/606438)
[JUNCTOPHILIN 3; JPH3](https://omim.org/entry/605268)
Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities progressing to death over ten to 20 years. In some individuals the presentation resembles juvenile-onset Huntington disease (HD), usually presenting in the fourth decade (ages 29 to 41 years) with diminished coordination and weight loss despite increase in food intake. Neurologic abnormalities include parkinsonism (rigidity, bradykinesia, tremor), dysarthria, and hyperreflexia. In others the presentation is more variable but, in general, corresponds to typical HD. [Gene Reviews, Huntington Disease-Like 2; 2018.06.21
Clinically similar to Huntington disease; in one well-studied pedigree, characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movements, psychiatric symptoms, weight loss, dementia, and relentless course with death about 20 years after disease onset. [from MIM:606438; 2018.06.21]
Huntington disease-like-2 (HDL2) can be caused by a heterozygous expanded CAG/CTG repeat in the junctophilin-3 gene (JPH3). Normal alleles contain 6 to 28 repeats, whereas pathogenic alleles contain over 41 repeats (Todd and Paulson, 2010; pubmed:20373340). [from MIM:606438; 2018.06.21]
JPH3 is brain-specific and appears to have an active role in certain neurons involved in motor coordination and memory. [Gene Cards, JPH3; 2021.02.28]
JPH3 isoform 2 length of the poly-Ala region is variable (6 to 27 CTG/CAG triplets) in the normal population and may be expanded (41 to 58 CTG/CAG triplets) in patients suffering from Huntington disease-like type 2. [UniProt, Q8WXH2; 2021.02.28]
The JPH3 gene encodes junctophilin-3, a member of a conserved family of proteins that are components of junctional complexes. Junctional complexes between the plasma membrane (PM) and endoplasmic/sarcoplasmic reticulum (ER/SR) are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels (Takeshima et al. 2000; pubmed:10949023). [from MIM:605268; 2018.06.21]
Many to one: 4 human genes to 1 Drosophila gene.
