Moyamoya disease 8

Summary

Moyamoya disease 8 (MONDO:0980949) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Moyamoya disease 8
Mondo ID	MONDO:0980949
OMIM	621469
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebrovascular disorder › intracranial arterial disease › cerebral arterial disease › Moyamoya disease › Moyamoya disease 8

Related subtypes (7): moyamoya disease 1, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, Moyamoya disease 2, moyamoya disease 3, Moyamoya disease 5, Moyamoya disease with early-onset achalasia, moyamoya disease 7

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4686577	NOS3, IVS12, G-C, +1	NOS3	Pathogenic	no assertion criteria provided
4686578	C648R	NOS3	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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
NANOS3	HGNC:22048	ENSG00000187556	P60323	Nanos homolog 3	clinvar
NOS3	HGNC:7876	ENSG00000164867	P29474	Nitric oxide synthase 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NANOS3	Nanos homolog 3	Plays a role in the maintenance of the undifferentiated state of germ cells regulating the spermatogonia cell cycle and inducing a prolonged transit in G1 phase.
NOS3	Nitric oxide synthase 3	Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NANOS3	Transcription factor	no		Nanos/Xcar2, Znf_nanos-typ, Nanos_sf
NOS3	Enzyme (other)	yes	1.14.13.39	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amygdala	1
prefrontal cortex	1
primordial germ cell in gonad	1
apex of heart	1
lower esophagus mucosa	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NANOS3	129	broad	yes	primordial germ cell in gonad, prefrontal cortex, amygdala
NOS3	168	broad	marker	spleen, apex of heart, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOS3	3,606
NANOS3	932

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOS3	P29474	105

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NANOS3	P60323	71.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NOSIP mediated eNOS trafficking	1	2855.0×	0.004	NOS3
NOSTRIN mediated eNOS trafficking	1	1142.0×	0.004	NOS3
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	571.0×	0.004	NOS3
eNOS activation	1	439.2×	0.004	NOS3
Specification of primordial germ cells	1	439.2×	0.004	NANOS3
Nitric oxide stimulates guanylate cyclase	1	407.9×	0.004	NOS3
VEGFR2 mediated vascular permeability	1	203.9×	0.008	NOS3
ROS and RNS production in phagocytes	1	167.9×	0.008	NOS3
Reproduction	1	95.2×	0.012	NANOS3
Extra-nuclear estrogen signaling	1	85.2×	0.012	NOS3
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.012	NOS3

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 the force of heart contraction by chemical signal	1	4213.0×	0.003	NOS3
negative regulation of muscle hyperplasia	1	4213.0×	0.003	NOS3
smooth muscle hyperplasia	1	4213.0×	0.003	NOS3
tetrahydrobiopterin metabolic process	1	4213.0×	0.003	NOS3
regulation of nervous system process	1	2808.7×	0.004	NOS3
regulation of systemic arterial blood pressure by endothelin	1	1404.3×	0.006	NOS3
L-arginine catabolic process	1	1404.3×	0.006	NOS3
ovulation from ovarian follicle	1	936.2×	0.006	NOS3
negative regulation of platelet activation	1	936.2×	0.006	NOS3
response to fluid shear stress	1	936.2×	0.006	NOS3
negative regulation of potassium ion transport	1	936.2×	0.006	NOS3
negative regulation of calcium ion transport	1	842.6×	0.006	NOS3
negative regulation of biomineral tissue development	1	766.0×	0.006	NOS3
nitric oxide metabolic process	1	702.2×	0.006	NOS3
obsolete nitric oxide mediated signal transduction	1	648.1×	0.006	NOS3
removal of superoxide radicals	1	526.6×	0.007	NOS3
regulation of sodium ion transport	1	468.1×	0.007	NOS3
pulmonary valve morphogenesis	1	468.1×	0.007	NOS3
endocardial cushion morphogenesis	1	421.3×	0.007	NOS3
nitric oxide biosynthetic process	1	351.1×	0.008	NOS3
mRNA destabilization	1	337.0×	0.008	NANOS3
negative regulation of blood pressure	1	324.1×	0.008	NOS3
negative regulation of smooth muscle cell proliferation	1	312.1×	0.008	NOS3
blood vessel diameter maintenance	1	312.1×	0.008	NOS3
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	290.6×	0.008	NOS3
negative regulation of apoptotic signaling pathway	1	280.9×	0.008	NANOS3
lipopolysaccharide-mediated signaling pathway	1	263.3×	0.008	NOS3
germ cell development	1	227.7×	0.008	NANOS3
homeostasis of number of cells within a tissue	1	221.7×	0.008	NOS3
aortic valve morphogenesis	1	216.1×	0.008	NOS3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
NOS3	CHLORZOXAZONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOS3	6	4
NANOS3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHLORZOXAZONE	4	NOS3
TILARGININE	3	NOS3
GW-274150	2	NOS3
PIMAGEDINE	2	NOS3
L-NAME	2	NOS3
NITROARGININE	1	NOS3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NOS3	188	Binding:178, ADMET:6, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NOS3	1.14.13.39	nitric-oxide synthase (NADPH)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NOS3	188

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

6 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)
CHLORZOXAZONE	4	NOS3
TILARGININE	3	NOS3
GW-274150	2	NOS3
PIMAGEDINE	2	NOS3
L-NAME	2	NOS3
NITROARGININE	1	NOS3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NOS3
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	NANOS3

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)
NANOS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.