Huntington disease-like 1

Summary

Huntington disease-like 1 (MONDO:0011299) is a disease caused by PRNP (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: PRNP (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 107
• Phenotypes (HPO): 44

Clinical features

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0002072	Chorea	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0000746	Delusion	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000298	Mask-like facies	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000514	Slow saccadic eye movements	Occasional (5-29%)
HP:0000570	Abnormal saccadic eye movements	Occasional (5-29%)
HP:0000617	Abnormality of ocular smooth pursuit	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002134	Abnormality of the basal ganglia	Occasional (5-29%)
HP:0002171	Gliosis	Occasional (5-29%)
HP:0002311	Incoordination	Occasional (5-29%)
HP:0002312	Clumsiness	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002375	Hypokinesia	Occasional (5-29%)
HP:0002457	Abnormal head movements	Occasional (5-29%)
HP:0002533	Abnormal posturing	Occasional (5-29%)
HP:0003043	Abnormality of the shoulder	Occasional (5-29%)
HP:0006801	Hyperactive deep tendon reflexes	Occasional (5-29%)
HP:0006961	Jerky head movements	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0008003	Jerky ocular pursuit movements	Occasional (5-29%)
HP:0011446	Abnormality of higher mental function	Occasional (5-29%)
HP:0040201	Simultanapraxia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Huntington disease-like 1
Mondo ID	MONDO:0011299
MeSH	C566398
OMIM	603218
Orphanet	157941
DOID	DOID:0090103
UMLS	C1864112
MedGen	355137
GARD	0016985
Is cancer (heuristic)	no

Also known as: early-onset prion disease with prominent psychiatric features · HDL1 · HLN1 · Huntington disease-like 1 · Huntington disease-like type 1 · Huntington-like neurodegenerative disorder 1 · neurodegenerative disease with chorea caused by mutation in PRNP · PRNP neurodegenerative disease with chorea

Data availability: 107 ClinVar variants · 2 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › prion disease › Huntington disease-like 1

Related subtypes (9): Creutzfeldt Jacob disease, kuru, scrapie, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, spongiform encephalopathy with neuropsychiatric features, familial Alzheimer-like prion disease, PrP systemic amyloidosis, sporadic fatal insomnia

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

107 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 31 likely benign, 10 benign/likely benign, 7 pathogenic, 6 conflicting classifications of pathogenicity, 6 benign, 3 likely pathogenic, 3 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
13394	NM_000311.5(PRNP):c.154_177[6_13]	PRNP	Pathogenic	no assertion criteria provided
13395	NM_000311.5(PRNP):c.305C>T (p.Pro102Leu)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13398	NM_000311.5(PRNP):c.598G>A (p.Glu200Lys)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13401	NM_000311.5(PRNP):c.593T>C (p.Phe198Ser)	PRNP	Pathogenic	criteria provided, multiple submitters, no conflicts
13403	NM_000311.5(PRNP):c.628G>A (p.Val210Ile)	PRNP	Pathogenic/Likely pathogenic/Pathogenic, low penetrance	criteria provided, multiple submitters, no conflicts
13407	NM_000311.5(PRNP):c.547A>G (p.Thr183Ala)	PRNP	Pathogenic	criteria provided, single submitter
13410	NM_000311.5(PRNP):c.392G>T (p.Gly131Val)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13411	NM_000311.5(PRNP):c.623G>A (p.Arg208His)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21148	NM_000311.5(PRNP):c.478C>T (p.Gln160Ter)	PRNP	Pathogenic	criteria provided, single submitter
2815837	NM_000311.5(PRNP):c.350_351inv (p.Ala117Val)	PRNP	Pathogenic	criteria provided, single submitter
39359	NM_000311.5(PRNP):c.532G>A (p.Asp178Asn)	PRNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13402	NM_000311.5(PRNP):c.650A>G (p.Gln217Arg)	PRNP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1507942	NM_000311.5(PRNP):c.443G>A (p.Arg148His)	PRNP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138330	NM_000311.5(PRNP):c.563C>G (p.Thr188Arg)	PRNP	Likely pathogenic	criteria provided, single submitter
1326274	NM_000311.5(PRNP):c.635A>C (p.Gln212Pro)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13405	NM_000311.5(PRNP):c.538G>A (p.Val180Ile)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
871373	NM_000311.5(PRNP):c.606C>T (p.Asp202=)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895060	NM_000311.5(PRNP):c.143G>A (p.Arg48His)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899176	NM_000311.5(PRNP):c.5C>T (p.Ala2Val)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899178	NM_000311.5(PRNP):c.116C>T (p.Pro39Leu)	PRNP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2422855	NC_000020.10:g.(?1959939)(6760201_?)dup	AP5S1	Uncertain significance	criteria provided, single submitter
1005336	NM_000311.5(PRNP):c.290G>A (p.Ser97Asn)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
13406	NM_000311.5(PRNP):c.695T>G (p.Met232Arg)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1398824	NM_000311.5(PRNP):c.452G>T (p.Arg151Leu)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1409171	NM_000311.5(PRNP):c.625G>A (p.Val209Met)	PRNP	Uncertain significance	criteria provided, single submitter
1409869	NM_000311.5(PRNP):c.622C>T (p.Arg208Cys)	PRNP	Uncertain significance	criteria provided, single submitter
1422522	NM_000311.5(PRNP):c.620A>G (p.Glu207Gly)	PRNP	Uncertain significance	criteria provided, single submitter
1468083	NM_000311.5(PRNP):c.498G>A (p.Met166Ile)	PRNP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1474931	NM_000311.5(PRNP):c.755T>C (p.Val252Ala)	PRNP	Uncertain significance	criteria provided, single submitter
1495663	NM_000311.5(PRNP):c.86G>A (p.Gly29Glu)	PRNP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 7 · 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
PRNP	Strong	Autosomal dominant	Huntington disease-like 1	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRNP	Orphanet:157941	Huntington disease-like 1
PRNP	Orphanet:280397	Familial Alzheimer-like prion disease
PRNP	Orphanet:282166	Inherited Creutzfeldt-Jakob disease
PRNP	Orphanet:356	Gerstmann-Straussler-Scheinker syndrome
PRNP	Orphanet:397606	PrP systemic amyloidosis
PRNP	Orphanet:454745	Kuru
PRNP	Orphanet:466	Fatal familial insomnia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRNP	HGNC:9449	ENSG00000171867	F7VJQ1	Alternative prion protein	gencc,clinvar
AP5S1	HGNC:15875	ENSG00000125843	Q9NUS5	AP-5 complex subunit sigma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AP5S1	AP-5 complex subunit sigma-1	As part of AP-5, a probable fifth adaptor protein complex it may be involved in endosomal transport.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRNP	Other/Unknown	no		Prion, Prion_copper_b_octapeptide, Prion/Doppel_prot_b-ribbon_dom
AP5S1	Other/Unknown	no		AP-5_subunit_s1

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
CA1 field of hippocampus	1
pigmented layer of retina	1
biceps brachii	1
primordial germ cell in gonad	1
skeletal muscle tissue of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRNP	294	ubiquitous	marker	CA1 field of hippocampus, Brodmann (1909) area 23, pigmented layer of retina
AP5S1	226	ubiquitous	marker	primordial germ cell in gonad, biceps brachii, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRNP	2,594
AP5S1	527

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRNP	F7VJQ1	70
AP5S1	Q9NUS5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	475.8×	0.004	PRNP
NCAM1 interactions	1	248.3×	0.004	PRNP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of glutamate receptor signaling pathway	1	1685.2×	0.006	PRNP
negative regulation of amyloid precursor protein catabolic process	1	1685.2×	0.006	PRNP
negative regulation of dendritic spine maintenance	1	1404.3×	0.006	PRNP
regulation of calcium ion import across plasma membrane	1	1404.3×	0.006	PRNP
positive regulation of glutamate receptor signaling pathway	1	766.0×	0.006	PRNP
dendritic spine maintenance	1	648.1×	0.006	PRNP
negative regulation of long-term synaptic potentiation	1	648.1×	0.006	PRNP
negative regulation of protein processing	1	561.7×	0.006	PRNP
neuron projection maintenance	1	561.7×	0.006	PRNP
negative regulation of interleukin-17 production	1	526.6×	0.006	PRNP
negative regulation of activated T cell proliferation	1	526.6×	0.006	PRNP
response to amyloid-beta	1	495.6×	0.006	PRNP
intracellular copper ion homeostasis	1	468.1×	0.006	PRNP
negative regulation of calcineurin-NFAT signaling cascade	1	468.1×	0.006	PRNP
negative regulation of amyloid-beta formation	1	443.5×	0.006	PRNP
response to cadmium ion	1	366.4×	0.007	PRNP
cellular response to copper ion	1	312.1×	0.007	PRNP
regulation of potassium ion transmembrane transport	1	312.1×	0.007	PRNP
negative regulation of interleukin-2 production	1	290.6×	0.007	PRNP
positive regulation of protein targeting to membrane	1	280.9×	0.007	PRNP
long-term memory	1	210.7×	0.009	PRNP
positive regulation of calcium-mediated signaling	1	210.7×	0.009	PRNP
cellular response to amyloid-beta	1	195.9×	0.009	PRNP
negative regulation of type II interferon production	1	191.5×	0.009	PRNP
negative regulation of T cell receptor signaling pathway	1	183.2×	0.009	PRNP
protein destabilization	1	145.3×	0.010	PRNP
positive regulation of neuron apoptotic process	1	135.9×	0.010	PRNP
positive regulation of protein localization to plasma membrane	1	135.9×	0.010	PRNP
endosomal transport	1	122.1×	0.011	AP5S1
learning or memory	1	120.4×	0.011	PRNP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRNP	0	0
AP5S1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	PRNP, AP5S1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRNP	0	—
AP5S1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.