Progressive supranuclear palsy-parkinsonism syndrome

Summary

Progressive supranuclear palsy-parkinsonism syndrome (MONDO:0009839) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 17
• Phenotypes (HPO): 20

Clinical features

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0002172	Postural instability	Very frequent (80-99%)
HP:0002548	Parkinsonism with favorable response to dopaminergic medication	Very frequent (80-99%)
HP:0000511	Vertical supranuclear gaze palsy	Very frequent (80-99%)
HP:0000570	Abnormal saccadic eye movements	Very frequent (80-99%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0006921	Axial muscle stiffness	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0002527	Falls	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002068	Neuromuscular dysphagia	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0000739	Anxiety	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive supranuclear palsy-parkinsonism syndrome
Mondo ID	MONDO:0009839
MeSH	C537240
OMIM	260540
Orphanet	240085
UMLS	C1850077
MedGen	342410
GARD	0017183
Is cancer (heuristic)	no

Also known as: atypical PSP · progressive supranuclear palsy atypical · PSP-p · PSP-parkinsonism · supranuclear palsy, progressive atypical

Data availability: 17 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive supranuclear palsy › atypical progressive supranuclear palsy syndrome › progressive supranuclear palsy-parkinsonism syndrome

Related subtypes (3): progressive supranuclear palsy-pure akinesia with gait freezing syndrome, progressive supranuclear palsy-corticobasal syndrome, progressive supranuclear palsy-progressive non-fluent aphasia syndrome

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

17 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 5 pathogenic, 2 benign/likely benign, 1 likely benign, 1 benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
14245	NM_001377265.1(MAPT):c.2078C>T (p.Pro693Leu)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14247	NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
14253	NM_001377265.1(MAPT):c.2013T>G (p.Asn671Lys)	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
98222	NM_001377265.1(MAPT):c.2091+16C>T	MAPT	Pathogenic	criteria provided, multiple submitters, no conflicts
98243	NM_001377265.1(MAPT):c.2060ATA[1] (p.Asn688del)	MAPT	Pathogenic	criteria provided, single submitter
98208	NM_001377265.1(MAPT):c.1891G>A (p.Ala631Thr)	MAPT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1345546	NM_001377265.1(MAPT):c.10C>A (p.Pro4Thr)	MAPT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1417517	NM_001377265.1(MAPT):c.1807C>T (p.Arg603Cys)	MAPT	Uncertain significance	criteria provided, multiple submitters, no conflicts
3582155	NM_001377265.1(MAPT):c.848G>A (p.Gly283Asp)	MAPT	Uncertain significance	criteria provided, single submitter
429936	NM_001377265.1(MAPT):c.1115C>T (p.Ala372Val)	MAPT	Uncertain significance	criteria provided, multiple submitters, no conflicts
452810	NM_001377265.1(MAPT):c.1042T>C (p.Ser348Pro)	MAPT	Uncertain significance	criteria provided, multiple submitters, no conflicts
4538486	NM_001377265.1(MAPT):c.709G>A (p.Gly237Ser)	MAPT	Uncertain significance	criteria provided, single submitter
956359	NM_001377265.1(MAPT):c.89C>T (p.Thr30Ile)	MAPT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1126880	NM_001377265.1(MAPT):c.1881G>A (p.Ser627=)	MAPT	Likely benign	criteria provided, multiple submitters, no conflicts
1271108	NM_001377265.1(MAPT):c.2074G>A (p.Val692Ile)	MAPT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
257504	NM_001377265.1(MAPT):c.220+2535A>G	MAPT	Benign	criteria provided, multiple submitters, no conflicts
98197	NM_001377265.1(MAPT):c.914A>G (p.Gln305Arg)	MAPT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
MAPT	Strong	Autosomal dominant	supranuclear palsy, progressive, 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAPT	Orphanet:100069	Semantic dementia
MAPT	Orphanet:100070	Progressive non-fluent aphasia
MAPT	Orphanet:240071	Classic progressive supranuclear palsy syndrome
MAPT	Orphanet:240085	Progressive supranuclear palsy-predominant parkinsonism syndrome
MAPT	Orphanet:240094	Progressive supranuclear palsy-pure akinesia with gait freezing syndrome
MAPT	Orphanet:240103	Progressive supranuclear palsy-corticobasal syndrome
MAPT	Orphanet:240112	Progressive supranuclear palsy-progressive non-fluent aphasia syndrome
MAPT	Orphanet:275864	Behavioral variant of frontotemporal dementia

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
MAPT	HGNC:6893	ENSG00000186868	P10636	Microtubule-associated protein tau	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAPT	Microtubule-associated protein tau	Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.

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)
MAPT	Other/Unknown	no		MAP_tubulin-bd_rpt, Tau, MAP2/MAP4/Tau

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
prefrontal cortex	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAPT	141	broad	marker	cortical plate, superior frontal gyrus, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAPT	7,289

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAPT	P10636	293

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Caspase-mediated cleavage of cytoskeletal proteins	1	951.7×	0.005	MAPT
Apoptotic cleavage of cellular proteins	1	475.8×	0.005	MAPT
Apoptotic execution phase	1	475.8×	0.005	MAPT
Activation of AMPK downstream of NMDARs	1	380.7×	0.005	MAPT
Apoptosis	1	167.9×	0.007	MAPT
Programmed Cell Death	1	146.4×	0.007	MAPT
PKR-mediated signaling	1	141.0×	0.007	MAPT

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
plus-end-directed organelle transport along microtubule	1	16852.0×	0.002	MAPT
neurofibrillary tangle assembly	1	8426.0×	0.002	MAPT
negative regulation of protein localization to mitochondrion	1	8426.0×	0.002	MAPT
rRNA metabolic process	1	4213.0×	0.002	MAPT
axonal transport	1	4213.0×	0.002	MAPT
positive regulation of protein localization to synapse	1	4213.0×	0.002	MAPT
negative regulation of mitochondrial fission	1	3370.4×	0.002	MAPT
regulation of long-term synaptic depression	1	3370.4×	0.002	MAPT
regulation of microtubule-based movement	1	2808.7×	0.002	MAPT
intracellular distribution of mitochondria	1	2407.4×	0.002	MAPT
regulation of mitochondrial fission	1	2106.5×	0.002	MAPT
cellular response to brain-derived neurotrophic factor stimulus	1	1872.4×	0.002	MAPT
generation of neurons	1	1532.0×	0.002	MAPT
negative regulation of mitochondrial membrane potential	1	1404.3×	0.002	MAPT
axonal transport of mitochondrion	1	1404.3×	0.002	MAPT
positive regulation of protein localization	1	1404.3×	0.002	MAPT
regulation of microtubule polymerization	1	1123.5×	0.002	MAPT
regulation of calcium-mediated signaling	1	1123.5×	0.002	MAPT
regulation of microtubule polymerization or depolymerization	1	1053.2×	0.002	MAPT
supramolecular fiber organization	1	1053.2×	0.002	MAPT
regulation of cellular response to heat	1	1053.2×	0.002	MAPT
astrocyte activation	1	991.3×	0.002	MAPT
protein polymerization	1	991.3×	0.002	MAPT
response to lead ion	1	936.2×	0.002	MAPT
regulation of chromosome organization	1	936.2×	0.002	MAPT
positive regulation of superoxide anion generation	1	887.0×	0.002	MAPT
microtubule polymerization	1	887.0×	0.002	MAPT
central nervous system neuron development	1	802.5×	0.002	MAPT
positive regulation of microtubule polymerization	1	674.1×	0.003	MAPT
microglial cell activation	1	624.1×	0.003	MAPT

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MAPT	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPT	449	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT
IDARUBICIN	4	MAPT
ACETAMINOPHEN	4	MAPT
ACITRETIN	4	MAPT
CISPLATIN	4	MAPT
CLOBETASOL PROPIONATE	4	MAPT
AMINOSALICYLIC ACID	4	MAPT
TETRABENAZINE	4	MAPT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MAPT	184	Binding:180, Functional:4

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAPT	184

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	MAPT
PHENYLBUTAZONE	4	MAPT
CEFOTAXIME SODIUM	4	MAPT
DIENESTROL	4	MAPT
PROGESTERONE	4	MAPT
CLOTRIMAZOLE	4	MAPT
CHOLECALCIFEROL	4	MAPT
LATANOPROST	4	MAPT
CHLORTHALIDONE	4	MAPT
FLUORESCEIN	4	MAPT
OXCARBAZEPINE	4	MAPT
NABUMETONE	4	MAPT
GLIPIZIDE	4	MAPT
AMIODARONE HYDROCHLORIDE	4	MAPT
TRICLABENDAZOLE	4	MAPT
MESORIDAZINE	4	MAPT
INDIGOTINDISULFONATE	4	MAPT
TRIHEXYPHENIDYL HYDROCHLORIDE	4	MAPT
IMIPRAMINE	4	MAPT
FURAZOLIDONE	4	MAPT
DROPERIDOL	4	MAPT
ARIPIPRAZOLE	4	MAPT
RALOXIFENE HYDROCHLORIDE	4	MAPT
IDARUBICIN	4	MAPT
ACETAMINOPHEN	4	MAPT
ACITRETIN	4	MAPT
CISPLATIN	4	MAPT
CLOBETASOL PROPIONATE	4	MAPT
AMINOSALICYLIC ACID	4	MAPT
TETRABENAZINE	4	MAPT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAPT
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.