PRKAR1B-related neurodegenerative dementia with intermediate filaments

Summary

PRKAR1B-related neurodegenerative dementia with intermediate filaments (MONDO:0018475) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000726	Dementia	Obligate (100%)
HP:0000719	Inappropriate behavior	Very frequent (80-99%)
HP:0002145	Frontotemporal dementia	Very frequent (80-99%)
HP:0002333	Motor deterioration	Very frequent (80-99%)
HP:0002354	Memory impairment	Very frequent (80-99%)
HP:0012757	Abnormal neuron morphology	Very frequent (80-99%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002172	Postural instability	Frequent (30-79%)
HP:0002362	Shuffling gait	Frequent (30-79%)
HP:0002463	Language impairment	Frequent (30-79%)
HP:0002506	Diffuse cerebral atrophy	Frequent (30-79%)
HP:0002527	Falls	Frequent (30-79%)
HP:0003552	Muscle stiffness	Frequent (30-79%)
HP:0007311	Short stepped shuffling gait	Frequent (30-79%)
HP:0010794	Impaired visuospatial constructive cognition	Frequent (30-79%)
HP:0030216	Inertia	Frequent (30-79%)
HP:0006892	Frontotemporal cerebral atrophy	Occasional (5-29%)
HP:0002503	Spinocerebellar tract degeneration	Excluded (0%)
HP:0007373	Motor neuron atrophy	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PRKAR1B-related neurodegenerative dementia with intermediate filaments
Mondo ID	MONDO:0018475
Orphanet	412066
UMLS	C4751505
MedGen	1654800
GARD	0021738
Is cancer (heuristic)	no

Data availability: 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › cognitive disorder › dementia › hereditary dementia › PRKAR1B-related neurodegenerative dementia with intermediate filaments

Related subtypes (14): neuronal intranuclear inclusion disease, hereditary sensory neuropathy-deafness-dementia syndrome, Alzheimer disease 17, Alzheimer disease 18, Huntington disease-like syndrome, frontotemporal dementia with motor neuron disease, frontotemporal dementia, neurodegeneration with brain iron accumulation, adrenoleukodystrophy, corticobasal syndrome, metachromatic leukodystrophy, posterior cortical atrophy, autosomal dominant cerebellar ataxia, familial Alzheimer disease

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
PRKAR1B	Supportive	Autosomal dominant	PRKAR1B-related neurodegenerative dementia with intermediate filaments	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRKAR1B	Orphanet:412066	PRKAR1B-related neurodegenerative dementia with intermediate filaments
PRKAR1B	Orphanet:692173	Marbach-Schaaf neurodevelopmental syndrome

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
PRKAR1B	HGNC:9390	ENSG00000188191	P31321	cAMP-dependent protein kinase type I-beta regulatory subunit	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKAR1B	cAMP-dependent protein kinase type I-beta regulatory subunit	Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in 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)
PRKAR1B	Other/Unknown	no		cNMP-bd_dom, cAMP_dep_PK_reg_su_I/II_a/b, cAMP_dep_PK_reg_su

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
Brodmann (1909) area 10	1
cingulate cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKAR1B	243	ubiquitous	marker	Brodmann (1909) area 10, right frontal lobe, cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRKAR1B	2,865

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PRKAR1B	P31321	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 48. 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
CREB1 phosphorylation through the activation of Adenylate Cyclase	1	878.5×	0.008	PRKAR1B
PKA activation in glucagon signalling	1	671.8×	0.008	PRKAR1B
PKA activation	1	634.4×	0.008	PRKAR1B
PKA-mediated phosphorylation of CREB	1	571.0×	0.008	PRKAR1B
DARPP-32 events	1	475.8×	0.008	PRKAR1B
Anti-inflammatory response favouring Leishmania parasite infection	1	393.8×	0.008	PRKAR1B
Leishmania parasite growth and survival	1	393.8×	0.008	PRKAR1B
Calmodulin induced events	1	380.7×	0.008	PRKAR1B
CaM pathway	1	380.7×	0.008	PRKAR1B
Ca-dependent events	1	368.4×	0.008	PRKAR1B
Aquaporin-mediated transport	1	368.4×	0.008	PRKAR1B
Glucagon signaling in metabolic regulation	1	346.1×	0.008	PRKAR1B
G-protein mediated events	1	326.3×	0.008	PRKAR1B
DAG and IP3 signaling	1	317.2×	0.008	PRKAR1B
Response of endothelial cells to shear stress	1	300.5×	0.008	PRKAR1B
FCGR3A-mediated IL10 synthesis	1	292.8×	0.008	PRKAR1B
Opioid Signalling	1	265.6×	0.008	PRKAR1B
PLC beta mediated events	1	265.6×	0.008	PRKAR1B
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.008	PRKAR1B
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.008	PRKAR1B
Cellular responses to mechanical stimuli	1	259.6×	0.008	PRKAR1B
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.008	PRKAR1B
GPER1 signaling	1	248.3×	0.008	PRKAR1B
Regulation of insulin secretion	1	219.6×	0.009	PRKAR1B
Post NMDA receptor activation events	1	203.9×	0.009	PRKAR1B
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.009	PRKAR1B
Signaling by Hedgehog	1	184.2×	0.009	PRKAR1B
Hedgehog ‘off’ state	1	178.4×	0.009	PRKAR1B
Integration of energy metabolism	1	175.7×	0.009	PRKAR1B
Leishmania infection	1	163.1×	0.009	PRKAR1B

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
positive regulation of fear response	1	16852.0×	7e-04	PRKAR1B
regulation of synaptic vesicle cycle	1	1123.5×	0.003	PRKAR1B
cellular response to glucagon stimulus	1	842.6×	0.003	PRKAR1B
vascular endothelial cell response to laminar fluid shear stress	1	732.7×	0.003	PRKAR1B
positive regulation of long-term synaptic potentiation	1	674.1×	0.003	PRKAR1B
negative regulation of inflammatory response to antigenic stimulus	1	601.9×	0.003	PRKAR1B
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.003	PRKAR1B
positive regulation of excitatory postsynaptic potential	1	526.6×	0.003	PRKAR1B
renal water homeostasis	1	510.7×	0.003	PRKAR1B
learning or memory	1	240.7×	0.005	PRKAR1B
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.010	PRKAR1B
chemical synaptic transmission	1	77.3×	0.013	PRKAR1B

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKAR1B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRKAR1B	1	Binding:1

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	PRKAR1B

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)
PRKAR1B	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.