Autosomal dominant striatal neurodegeneration type 1

Summary

Autosomal dominant striatal neurodegeneration type 1 (MONDO:0012205) is a disease caused by PDE8B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: PDE8B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 98

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant striatal neurodegeneration type 1
Mondo ID	MONDO:0012205
OMIM	609161
SNOMED CT	725392005
UMLS	C4310808
MedGen	934775
GARD	0024853
Is cancer (heuristic)	no

Also known as: ADSD · ADSD1 · PDE8B striatal degeneration, autosomal dominant · striatal degeneration, autosomal dominant · striatal Degeneration, autosomal dominant 1 · striatal degeneration, autosomal dominant 1 · striatal degeneration, autosomal dominant caused by mutation in PDE8B

Data availability: 98 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 › synucleinopathy › multiple system atrophy › striatonigral degeneration › striatal degeneration, autosomal dominant › autosomal dominant striatal neurodegeneration type 1

Related subtypes (1): striatal degeneration, autosomal dominant 2

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

98 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 31 benign, 11 benign/likely benign, 8 likely benign, 6 conflicting classifications of pathogenicity, 2 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
235862	NM_003719.5(PDE8B):c.79del (p.Arg27fs)	PDE8B	Pathogenic	no assertion criteria provided
6391	NM_003719.5(PDE8B):c.94_95delinsC (p.Val32fs)	PDE8B	Pathogenic	no assertion criteria provided
235863	NM_003719.5(PDE8B):c.304G>T (p.Glu102Ter)	PDE8B	Likely pathogenic	criteria provided, single submitter
2505562	NM_003719.5(PDE8B):c.1276C>T (p.Arg426Ter)	PDE8B	Likely pathogenic	criteria provided, single submitter
354147	NM_003719.5(PDE8B):c.156C>T (p.Ala52=)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354156	NM_003719.5(PDE8B):c.999A>G (p.Thr333=)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
354160	NM_003719.5(PDE8B):c.1309C>T (p.Arg437Cys)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907272	NM_003719.5(PDE8B):c.593C>T (p.Ser198Leu)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907273	NM_003719.5(PDE8B):c.796C>T (p.Arg266Trp)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907334	NM_003719.5(PDE8B):c.2139T>C (p.Tyr713=)	PDE8B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3341432	NM_003719.5(PDE8B):c.133G>C (p.Val45Leu)	PDE8B	Uncertain significance	criteria provided, multiple submitters, no conflicts
354142	NM_003719.5(PDE8B):c.-24C>T	PDE8B	Uncertain significance	criteria provided, single submitter
354144	NM_003719.5(PDE8B):c.52C>A (p.Arg18=)	PDE8B	Uncertain significance	criteria provided, single submitter
354146	NM_003719.5(PDE8B):c.125G>C (p.Gly42Ala)	PDE8B	Uncertain significance	criteria provided, multiple submitters, no conflicts
354148	NM_003719.5(PDE8B):c.280A>G (p.Arg94Gly)	PDE8B	Uncertain significance	criteria provided, multiple submitters, no conflicts
354167	NM_003719.5(PDE8B):c.2115C>T (p.Phe705=)	PDE8B	Uncertain significance	criteria provided, single submitter
354174	NM_003719.5(PDE8B):c.2545G>A (p.Asp849Asn)	PDE8B	Uncertain significance	criteria provided, multiple submitters, no conflicts
354176	NM_003719.5(PDE8B):c.*28C>G	PDE8B	Uncertain significance	criteria provided, single submitter
354181	NM_003719.5(PDE8B):c.*179G>A	PDE8B	Uncertain significance	criteria provided, single submitter
354182	NM_003719.5(PDE8B):c.*287C>T	PDE8B	Uncertain significance	criteria provided, single submitter
354184	NM_003719.5(PDE8B):c.*436C>T	PDE8B	Uncertain significance	criteria provided, single submitter
354197	NM_003719.5(PDE8B):c.*831T>C	PDE8B	Uncertain significance	criteria provided, single submitter
354203	NM_003719.5(PDE8B):c.*921A>G	PDE8B	Uncertain significance	criteria provided, single submitter
354205	NM_003719.5(PDE8B):c.*1011A>G	PDE8B	Uncertain significance	criteria provided, single submitter
354207	NM_003719.5(PDE8B):c.*1150A>G	PDE8B	Uncertain significance	criteria provided, single submitter
354209	NM_003719.5(PDE8B):c.*1520T>C	PDE8B	Uncertain significance	criteria provided, single submitter
354211	NM_003719.5(PDE8B):c.*1606T>C	PDE8B	Uncertain significance	criteria provided, single submitter
903931	NM_003719.5(PDE8B):c.1001G>A (p.Cys334Tyr)	PDE8B	Uncertain significance	criteria provided, multiple submitters, no conflicts
903933	NM_003719.5(PDE8B):c.1207A>G (p.Thr403Ala)	PDE8B	Uncertain significance	criteria provided, single submitter
903934	NM_003719.5(PDE8B):c.1211A>T (p.Glu404Val)	PDE8B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
PDE8B	Strong	Autosomal dominant	autosomal dominant striatal neurodegeneration type 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PDE8B	Orphanet:228169	Autosomal dominant striatal neurodegeneration
PDE8B	Orphanet:647782	Isolated micronodular adrenocortical disease

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
PDE8B	HGNC:8794	ENSG00000113231	O95263	High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PDE8B	High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PDE8B	Transcription factor	no	3.1.4.53	PAS, PDEase_catalytic_dom, HD/PDEase_dom

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
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PDE8B	170		marker	left lobe of thyroid gland, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDE8B	648

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PDE8B	O95263	74.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
G alpha (s) signalling events	1	73.2×	0.014	PDE8B

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
negative regulation of steroid hormone biosynthetic process	1	16852.0×	6e-04	PDE8B
operant conditioning	1	2407.4×	0.001	PDE8B
cAMP catabolic process	1	1872.4×	0.001	PDE8B
negative regulation of insulin secretion involved in cellular response to glucose stimulus	1	1685.2×	0.001	PDE8B
negative regulation of cAMP/PKA signal transduction	1	601.9×	0.003	PDE8B
behavioral fear response	1	432.1×	0.004	PDE8B
neuromuscular process controlling balance	1	330.4×	0.004	PDE8B
visual learning	1	306.4×	0.004	PDE8B
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.013	PDE8B
signal transduction	1	16.1×	0.062	PDE8B

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
PDE8B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PDE8B	35	Binding:33, ADMET:1, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE8B	3.1.4.53	3’,5’-cyclic-AMP phosphodiesterase

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	PDE8B

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)
PDE8B	35	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.