Premature ovarian failure 1

Summary

Premature ovarian failure 1 (MONDO:0010706) is a disease caused by FMR1 (GenCC Definitive), with 4 cohort genes and 9 clinical trials. Top therapeutic interventions include estrogens, conjugated, progesterone, and proline.

At a glance

• Causal gene: FMR1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 12
• Clinical trials: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	premature ovarian failure 1
Mondo ID	MONDO:0010706
OMIM	311360
Orphanet	642691
DOID	DOID:0080857
UMLS	C4552079
MedGen	1644269
GARD	0002811
Is cancer (heuristic)	no

Also known as: familial premature ovarian failure · FMR1 primary ovarian failure · FMR1-related premature ovarian failure · FMR1-related primary ovarian insufficiency · fragile X-associated primary ovarian insufficiency · fragile x-associated primary ovarian insufficiency · idiopathic familial premature ovarian failure · ovarian failure, premature · Pof1 · premature ovarian failure 1 · premature ovarian failure type 1 · primary ovarian failure caused by mutation in FMR1

Data availability: 12 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited primary ovarian failure › premature ovarian failure 1

Related subtypes (40): blepharophimosis, ptosis, and epicanthus inversus syndrome, congenital lipoid adrenal hyperplasia due to STAR deficency, ataxia telangiectasia, classic galactosemia, 46 XX gonadal dysgenesis, premature ovarian failure 2A, premature ovarian failure 2B, Satoyoshi syndrome, premature ovarian failure 3, osteosclerosis-ichthyosis-premature ovarian failure syndrome, premature ovarian failure 5, premature ovarian failure 6, premature ovarian failure 7, aromatase deficiency, premature ovarian failure 8, premature ovarian failure 9, 46,XX ovarian dysgenesis-short stature syndrome, premature ovarian failure 11, premature ovarian failure 12, Perrault syndrome, trisomy X, Turner syndrome, tetrasomy X, X small rings, premature ovarian failure 17, premature ovarian failure 18, premature ovarian failure 20, premature ovarian failure 19, premature ovarian failure 16, premature ovarian failure 13, premature ovarian failure 10, premature ovarian failure 14, premature ovarian failure 15, premature ovarian failure 4, premature ovarian failure 21, premature ovarian failure 22, premature ovarian failure 23, premature ovarian failure 24, premature ovarian failure 25, premature ovarian failure 26

Subtypes (1): symptomatic form of fragile X syndrome in female carrier

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

12 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 benign, 2 benign/likely benign, 2 uncertain significance, 1 not provided, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
623467	NM_002024.6(FMR1):c.-128GGC[55_200]	FMR1	Pathogenic	criteria provided, single submitter
9972	NM_002024.6:c.-128GGM[55_?]	FMR1	Pathogenic	no assertion criteria provided
156587	NM_017696.3(MCM9):c.1732+2T>C	MCM9	Pathogenic	criteria provided, single submitter
156588	NM_017696.3(MCM9):c.394C>T (p.Arg132Ter)	MCM9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
766072	NM_002024.6(FMR1):c.-129CGG[9]	FMR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1701686	NM_002024.6(FMR1):c.413G>A (p.Arg138Gln)	FMR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
521313	NM_002024.6(FMR1):c.1580G>A (p.Arg527His)	FMR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
129104	NM_002024.6(FMR1):c.433G>T (p.Ala145Ser)	FMR1	Benign	criteria provided, multiple submitters, no conflicts
587984	NM_002024.6(FMR1):c.18G>T (p.Val6=)	FMR1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
94023	NM_002024.6(FMR1):c.414G>A (p.Arg138=)	FMR1	Benign	criteria provided, multiple submitters, no conflicts
167875	NM_001436401.1(NOBOX):c.94C>T (p.Arg32Trp)	NOBOX	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
156586	NM_017696.3(MCM9):c.1533C>A (p.Tyr511Ter)	MCM9	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · 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
FMR1	Definitive	X-linked	premature ovarian failure 1	14
COL4A6	Limited	X-linked	premature ovarian failure 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FMR1	Orphanet:261483	Xq27.3q28 duplication syndrome
FMR1	Orphanet:642691	Fragile X-associated primary ovarian insufficiency
FMR1	Orphanet:908	Fragile X syndrome
FMR1	Orphanet:93256	Fragile X-associated tremor/ataxia syndrome
COL4A6	Orphanet:1018	X-linked Alport syndrome-diffuse leiomyomatosis
COL4A6	Orphanet:90625	Rare X-linked non-syndromic sensorineural deafness type DFN
MCM9	Orphanet:444048	46,XX ovarian dysgenesis-short stature syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FMR1	HGNC:3775	ENSG00000102081	Q06787	Fragile X messenger ribonucleoprotein 1	gencc,clinvar
COL4A6	HGNC:2208	ENSG00000197565	Q14031	Collagen alpha-6(IV) chain	gencc
MCM9	HGNC:21484	ENSG00000111877	Q9NXL9	DNA helicase MCM9	clinvar
NOBOX	HGNC:22448	ENSG00000106410	O60393	Homeobox protein NOBOX	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FMR1	Fragile X messenger ribonucleoprotein 1	Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsyn…
COL4A6	Collagen alpha-6(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
MCM9	DNA helicase MCM9	Component of the MCM8-MCM9 complex, which is involved in the repair of double-stranded DNA breaks (DBSs) and DNA interstrand cross-links (ICLs) by homologous recombination (HR).
NOBOX	Homeobox protein NOBOX	Transcription factor which may play a role in oogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · 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	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FMR1	Other/Unknown	no		KH_dom, KH_dom_type_1, Agenet-like_dom
COL4A6	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
MCM9	Other/Unknown	no		MCM_dom, AAA+_ATPase, NA-bd_OB-fold
NOBOX	Transcription factor	no		HD, Homeodomain-like_sf, NOBOX

Expression context

Cohort genes with no expression data: 0.

3 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)	1
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
sural nerve	1
lower esophagus	1
lower esophagus muscularis layer	1
mucosa of stomach	1
bronchial epithelial cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
colonic epithelium	1
granulocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FMR1	296	ubiquitous	marker	caput epididymis, corpus epididymis, sural nerve
COL4A6	197	broad	marker	mucosa of stomach, lower esophagus muscularis layer, lower esophagus
MCM9	233	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis
NOBOX	8		yes	primordial germ cell in gonad, colonic epithelium, granulocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FMR1	4,726
MCM9	2,092
COL4A6	1,535
NOBOX	855

Intra-cohort edges

A	B	Sources
FMR1	NOBOX	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FMR1	Q06787	12
MCM9	Q9NXL9	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL4A6	Q14031	48.27
NOBOX	O60393	48.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 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
Anchoring fibril formation	1	380.7×	0.012	COL4A6
Fibronectin matrix formation	1	285.5×	0.012	COL4A6
Crosslinking of collagen fibrils	1	285.5×	0.012	COL4A6
Attachment of bacteria to epithelial cells	1	248.3×	0.012	COL4A6
Attenuation phase	1	203.9×	0.012	COL4A6
Laminin interactions	1	190.3×	0.012	COL4A6
HSF1 activation	1	190.3×	0.012	COL4A6
M-decay: degradation of maternal mRNAs by maternally stored factors	1	163.1×	0.012	NOBOX
HSF1-dependent transactivation	1	158.6×	0.012	COL4A6
Collagen chain trimerization	1	129.8×	0.013	COL4A6
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.015	COL4A6
Collagen degradation	1	87.8×	0.015	COL4A6
Collagen biosynthesis and modifying enzymes	1	85.2×	0.015	COL4A6
Non-integrin membrane-ECM interactions	1	77.2×	0.015	COL4A6
ECM proteoglycans	1	75.1×	0.015	COL4A6
Regulation of HSF1-mediated heat shock response	1	69.6×	0.015	COL4A6
Integrin cell surface interactions	1	67.2×	0.015	COL4A6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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 intracellular transport of viral material	1	4213.0×	0.006	FMR1
recombinational interstrand cross-link repair	1	2106.5×	0.006	MCM9
mismatch repair involved in maintenance of fidelity involved in DNA-dependent DNA replication	1	2106.5×	0.006	MCM9
negative regulation of miRNA-mediated gene silencing	1	1404.3×	0.006	FMR1
regulation of translation at presynapse, modulating synaptic transmission	1	1404.3×	0.006	FMR1
negative regulation of long-term synaptic depression	1	1404.3×	0.006	FMR1
regulation of neuronal action potential	1	1053.2×	0.006	FMR1
negative regulation of voltage-gated calcium channel activity	1	842.6×	0.006	FMR1
negative regulation of synaptic vesicle exocytosis	1	842.6×	0.006	FMR1
host-mediated perturbation of viral RNA genome replication	1	702.2×	0.007	FMR1
positive regulation of miRNA-mediated gene silencing	1	601.9×	0.007	FMR1
positive regulation of long-term neuronal synaptic plasticity	1	468.1×	0.008	FMR1
regulation of dendritic spine development	1	421.3×	0.008	FMR1
negative regulation of cytoplasmic translation	1	421.3×	0.008	FMR1
collagen-activated tyrosine kinase receptor signaling pathway	1	324.1×	0.010	COL4A6
membraneless organelle assembly	1	280.9×	0.010	FMR1
regulation of filopodium assembly	1	263.3×	0.010	FMR1
positive regulation of proteasomal protein catabolic process	1	247.8×	0.011	FMR1
glutamate receptor signaling pathway	1	234.1×	0.011	FMR1
negative regulation of translational initiation	1	221.7×	0.011	FMR1
female gamete generation	1	200.6×	0.011	MCM9
regulation of neurotransmitter secretion	1	191.5×	0.011	FMR1
positive regulation of dendritic spine development	1	191.5×	0.011	FMR1
animal organ development	1	183.2×	0.011	FMR1
positive regulation of receptor internalization	1	175.5×	0.011	FMR1
regulatory ncRNA-mediated gene silencing	1	168.5×	0.011	FMR1
stress granule assembly	1	150.5×	0.012	FMR1
protein localization to chromatin	1	145.3×	0.012	MCM9
positive regulation of filopodium assembly	1	140.4×	0.012	FMR1
regulation of mRNA stability	1	105.3×	0.015	FMR1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FMR1	0	0
COL4A6	0	0
MCM9	0	0
NOBOX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	FMR1, COL4A6, MCM9, NOBOX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FMR1	0	—
COL4A6	0	—
MCM9	0	—
NOBOX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2/PHASE3	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT07117682	Not specified	NOT_YET_RECRUITING	Safety and Efficacy of Autologous Adipose-Derived Regenerative Cells (ADRCs) Injection for Improving Diminished Ovarian Reserve
NCT00471731	Not specified	COMPLETED	Dry Eye in Women With Turner Syndrome and Women With Premature Ovarian Failure
NCT01023178	Not specified	COMPLETED	Comparison of Transdermal and Oral Estrogens in Adolescent Girls With Ovarian Failure
NCT01177891	Not specified	COMPLETED	Genetic Analysis of Familial Cases of Premature Ovarian Failure
NCT02780791	Not specified	TERMINATED	Maturation of Follicles After Transplantation of Ovarian Tissue Into the Pelvic Wall and the Ovary
NCT05443282	Not specified	COMPLETED	Ovarian Reserve and Matrix Metalloproteinases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ESTROGENS, CONJUGATED	4	1
PROGESTERONE	4	1
PROLINE	2	1
CHEMBL352418	0	1