Huntington disease-like 2

Summary

Huntington disease-like 2 (MONDO:0011671) is a disease caused by JPH3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: JPH3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 5
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000751	Personality changes	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002060	Abnormal cerebral morphology	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002476	Primitive reflex	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0004305	Involuntary movements	Occasional (5-29%)
HP:0010994	Abnormal corpus striatum morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Huntington disease-like 2
Mondo ID	MONDO:0011671
MeSH	C564708
OMIM	606438
Orphanet	98934
DOID	DOID:0090104
SNOMED CT	721228006
UMLS	C1847987
MedGen	341120
GARD	0016874
Is cancer (heuristic)	no

Also known as: HDL2 · Huntington disease-like 2 · Huntington disease-like type 2

Data availability: 5 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › Huntington disease-like 2

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
5119	NM_001271604.4(JPH3):c.431CWG[41_?]	JPH3	Pathogenic	no assertion criteria provided
779279	NM_020655.4(JPH3):c.626G>C (p.Ser209Thr)	JPH3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3358991	NM_020655.4(JPH3):c.2101dup (p.Gln701fs)	JPH3	Uncertain significance	criteria provided, single submitter
548586	NM_020655.4(JPH3):c.955C>T (p.Arg319Trp)	JPH3	Uncertain significance	criteria provided, multiple submitters, no conflicts
778648	NM_020655.4(JPH3):c.1398T>C (p.Thr466=)	JPH3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
JPH3	Definitive	Autosomal dominant	Huntington disease-like 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
JPH3	Orphanet:98934	Huntington disease-like 2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
JPH3	HGNC:14203	ENSG00000154118	Q8WXH2	Junctophilin-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
JPH3	Junctophilin-3	Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
JPH3	Other/Unknown	no		MORN, Junctophilin

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parietal lobe	1
postcentral gyrus	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
JPH3	166	broad	yes	right frontal lobe, postcentral gyrus, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
JPH3	2,542

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
JPH3	Q8WXH2	61.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
locomotion	1	1532.0×	0.003	JPH3
regulation of cardiac muscle contraction by calcium ion signaling	1	1296.3×	0.003	JPH3
calcium ion transport into cytosol	1	1203.7×	0.003	JPH3
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.003	JPH3
regulation of neuronal synaptic plasticity	1	674.1×	0.003	JPH3
exploration behavior	1	648.1×	0.003	JPH3
neuromuscular process controlling balance	1	330.4×	0.004	JPH3
learning	1	280.9×	0.004	JPH3
regulation of synaptic plasticity	1	259.3×	0.004	JPH3
memory	1	183.2×	0.005	JPH3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
JPH3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	JPH3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
JPH3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.