Premature Ovarian Failure 20

Mendelian MONDO:0030975 Pathograph 15 Show in embeddings browser Primary Ovarian Insufficiency Meiotic Disorder

Premature ovarian failure 20 (POF20; OMIM 619938) is an autosomal recessive form of primary ovarian insufficiency caused by biallelic loss-of-function variants in MSH4 (MutS homolog 4). MSH4 is a meiosis-specific MutS homolog that heterodimerizes with MSH5 to form the MutS-gamma complex, which binds and stabilizes recombination intermediates during meiotic prophase I, promotes homologous chromosome synapsis, and acts with MLH1 at sites that mature into crossovers. Reported pathogenic alleles are splice-site, nonsense, frameshift, and missense variants, several of which remove or perturb the conserved C-terminal ATPase domain (Walker B motif and MutS signature). Biallelic loss is thought to cause oocyte meiotic failure and depletion of the ovarian follicle pool, presenting as amenorrhea (most often secondary) and infertility in 46,XX individuals; milder presentations with diminished ovarian reserve and poor oocyte quality have also been reported. Affected brothers in the same families have non-obstructive azoospermia with meiotic arrest, which MONDO classifies separately as spermatogenic failure 2.

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👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry homozygous or compound-heterozygous MSH4 variants; heterozygous parents are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28541421 SUPPORT Human clinical
"Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4). The variant followed a strict mendelian segregation within the family"
Homozygous MSH4 variant segregating with POI in the founding family.
PMID:38175272 SUPPORT Human clinical
"It was also observed that all affected members had homozygous mutations, while their parents were heterozygous and the fertile sister had no mutant allele, corresponding to autosomal recessive inheritance."
Segregation of a homozygous MSH4 nonsense variant with gonadal failure, with unaffected heterozygous parents.
⚙

Pathophysiology

4
MSH4 Loss of Function
Biallelic MSH4 variants remove or disrupt the MSH4 protein, most often in its C-terminal ATPase domain, inactivating the MSH4-MSH5 (MutS-gamma) heterodimer that recognizes and stabilizes Holliday junction recombination intermediates in meiotic prophase I.
MSH4 hgnc:7327 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MSH4 (hgnc:7327). hgnc:7327 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
ATP hydrolysis activity GO:0016887 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP hydrolysis activity (GO:0016887). GO:0016887 is a molecular function from the Gene Ontology.
Downstream
Defective Homolog Synapsis and Meiotic Recombination
Show evidence (3 references)
PMID:28541421 SUPPORT In vitro / ex vivo
"Exon trapping experiments showed that the splice-site mutation induced skipping of exon 17."
Splicing assay of the founding allele; the resulting in-frame deletion removes the Walker B ATPase motif, which the authors predict inactivates MSH4.
PMID:33448284 SUPPORT BACKGROUND Human clinical
"Along with its heterodimer partner MSH5, it is responsible for double-strand Holliday junction recognition and stabilization, to ensure accurate chromosome segregation during meiosis."
States the normal MutS-gamma function that the disease alleles remove.
PMID:30467025 SUPPORT INDIRECT In vitro / ex vivo
"Similar to the human protein, Sc Msh4-Msh5 exhibits the highest affinity for the HJ with a Kd < 0.4 nM in solution."
Purified yeast MutS-gamma binds Holliday junctions most tightly, as the human complex does; the structural role is inferred for human MSH4.
Defective Homolog Synapsis and Meiotic Recombination
Without MutS-gamma, homologous chromosomes fail to pair and synapse normally, and recombination intermediates are not channelled into MLH1-marked crossovers.
oocyte CL:0000023 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oocyte (CL:0000023). CL:0000023 is a cell type from the Cell Ontology.
homologous chromosome pairing at meiosis GO:0007129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased homologous chromosome pairing at meiosis (GO:0007129). GO:0007129 is a biological process from the Gene Ontology. synaptonemal complex assembly GO:0007130 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased synaptonemal complex assembly (GO:0007130). GO:0007130 is a biological process from the Gene Ontology. reciprocal meiotic recombination GO:0007131 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased reciprocal meiotic recombination (GO:0007131). GO:0007131 is a biological process from the Gene Ontology.
Animal models
Msh4 knockout mouse Mouse recapitulates Null mice show the meiotic pairing defect expected from the human loss-of-function alleles.
Downstream
Meiotic Arrest and Germ Cell Loss
Show evidence (2 references)
PMID:10809667 SUPPORT Model organism
"Our results show that MSH4 localization on chromosomes during the early stages of meiosis is essential for normal chromosome synapsis in prophase I and that it acts in the same pathway as MSH5."
Mouse genetics place MSH4 upstream of synapsis, in the MSH5 pathway.
PMID:10928988 SUPPORT In vitro / ex vivo
"These results suggest that MSH4 is first required for chromosome synapsis and that this MutS homologue is involved later with MLH1 in meiotic reciprocal recombination."
MSH4 interacts with MLH1 and colocalizes with it on synaptonemal complexes, linking MSH4 to crossover formation.
Meiotic Arrest and Germ Cell Loss
Germ cells that cannot complete synapsis and recombination arrest in meiotic prophase I and are eliminated, so functional gametes are not produced in either sex.
germ cell CL:0000586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germ cell (CL:0000586). CL:0000586 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Animal models
Msh4 knockout mouse Mouse recapitulates Unpaired oocytes undergo apoptosis shortly after birth.
Downstream
Ovarian Follicle Depletion
Show evidence (2 references)
PMID:10809667 SUPPORT Model organism
"Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure."
Msh4-null mice of both sexes are sterile from meiotic failure.
PMID:10809667 SUPPORT Model organism
"The failure of pairing in these oocytes correlated with an induction of apoptosis, resulting in the almost complete obliteration of germ cell numbers within the ovaries of Msh4−/− females by day 4 pp"
In female knockout mice, unpaired oocytes undergo apoptosis and are almost all lost within days of birth.
Ovarian Follicle Depletion
Loss of oocytes depletes the ovarian follicle pool. Depending on residual reserve, women present with amenorrhea and premature ovarian insufficiency, or with diminished ovarian reserve and poor oocyte yield and quality in assisted reproduction.
oocyte CL:0000023 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oocyte (CL:0000023). CL:0000023 is a cell type from the Cell Ontology.
female gamete generation GO:0007292 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased female gamete generation (GO:0007292). GO:0007292 is a biological process from the Gene Ontology.
Animal models
Msh4 knockout mouse Mouse partially recapitulates Female knockouts lose the oocyte pool and then the ovary itself.
Downstream
Premature ovarian insufficiency
Secondary amenorrhea
Female infertility
Elevated circulating follicle stimulating hormone level Loss of follicles removes ovarian negative feedback on the pituitary.
Show evidence (2 references)
PMID:37620942 SUPPORT Human clinical
"Our findings indicate a correlation between MSH4 variants and reduced oocyte quality, as well as abnormal morphology of the first polar body, thereby expanding the phenotypic spectrum associated with MSH4 variants."
A compound-heterozygous patient with diminished ovarian reserve had poor oocyte quantity and quality, the milder end of follicle depletion.
PMID:10809667 SUPPORT Model organism
"As in the case of Msh5−/− females, the loss of the oocyte pool resulted in the disruption of ovarian development and the complete loss of ovarian structures in the adult Msh4−/− female."
The mouse shows the extreme of follicle depletion, with no adult ovary.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Premature Ovarian Failure 20 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

4
Endocrine 1
Elevated circulating follicle stimulating hormone level HP:0008232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating follicle stimulating hormone level (HP:0008232). HP:0008232 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37620942 SUPPORT Human clinical
"The basic hormone levels of the proband were as follows: follicle-stimulating hormone (FSH), 29.86 mIU/mL"
FSH well above the 3-12 mIU/mL normal range the same paper gives, in a woman with biallelic MSH4 variants.
PMID:37620942 SUPPORT Human clinical
"Normal range of AFC: 7–20; Follicle-stimulating hormone: 3–12 mIU/mL"
Reference range the authors used to flag the FSH value as abnormal.
PMID:28541421 SUPPORT BACKGROUND Human clinical
"characterized by an early cessation of menses and high FSH levels"
Defines POI by high FSH in the paper that reported the founding MSH4 family.
Genitourinary 3
Premature ovarian insufficiency HP:0008209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature ovarian insufficiency (HP:0008209), qualified as young adult onset. HP:0008209 is a phenotype from the Human Phenotype Ontology.
Onset: YOUNG ADULT
Show evidence (3 references)
PMID:28541421 SUPPORT Human clinical
"Our study describes the first MSH4 mutation associated with POI"
POI in the founding homozygous family.
PMID:33448284 SUPPORT Human clinical
"Patients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L"
POI in an independent homozygous family.
PMID:34755185 SUPPORT Human clinical
"Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI."
POI in the sister of an MSH4-variant man with meiotic arrest.
Secondary amenorrhea HP:0000869 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary amenorrhea (HP:0000869). HP:0000869 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42386447 SUPPORT REVIEW SYNTHESIS Human clinical
"Affected individuals predominantly present with secondary amenorrhoea, with emerging evidence for milder phenotypes, including diminished ovarian reserve (DOR)."
Literature review of MSH4/MSH5 POI cases; the review pools MSH4 and MSH5 patients.
Female infertility HP:0008222 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Female infertility (HP:0008222). HP:0008222 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37620942 SUPPORT Human clinical
"The patient presented with poor oocyte quantity and quality, resulting in unsuccessful in vitro fertilization cycles."
Infertility with failed IVF in a woman with biallelic MSH4 variants.
PMID:38175272 SUPPORT Human clinical
"The results show that the testicular sperm retrieval and ovarian stimulation cycles have not been successful yet."
Review of reported MSH4 cases notes unsuccessful ovarian stimulation.
🧬

Genetic Associations

1
MSH4 (Causal)
Gene: MSH4 hgnc:7327 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MSH4 (hgnc:7327). hgnc:7327 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:28541421 SUPPORT Human clinical
"Our study describes the first MSH4 mutation associated with POI and increases the number of meiotic/DNA repair genes formally implicated as being responsible for this condition."
First report establishing MSH4 as a POI gene.
PMID:42386447 SUPPORT REVIEW SYNTHESIS Human clinical
"Biallelic MSH4 variants are well-established causes of POI and non-obstructive azoospermia (NOA), with MSH4 recognised as a high-evidence gene on clinical panels."
Review summarizing the accumulated case evidence that biallelic MSH4 variants cause POI.
PMID:36099812 SUPPORT Human clinical
"We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families."
A large POI cohort independently confirms MSH4 as a POI gene.
+ 1 more reference
Variants (4)
Exon 17 donor splice-site variant (p.Ile743_Lys785del)
Homozygous donor splice-site variant in a Colombian family; exon 17 skipping removes the Walker B motif of the ATPase domain.
Show evidence (1 reference)
PMID:28541421 SUPPORT In vitro / ex vivo
"Exon trapping experiments showed that the splice-site mutation induced skipping of exon 17. At the protein level, the mutation p.Ile743_Lys785del is predicted to lead to the ablation of the highly conserved Walker B motif of the ATP-binding domain, thus inactivating MSH4."
Functional splicing assay showing loss of the Walker B motif.
p.Ser754Leu
Homozygous missense in the MutS signature motif adjacent to the Walker B motif, found in a consanguineous Iranian family with both POI and NOA.
Show evidence (1 reference)
PMID:33448284 SUPPORT Human clinical
"Patients with primary ovarian insufficiency (POI) and non-obstructive azoospermia (NOA) were homozygous for the rare missense variant p. S754L located in the highly conserved MSH4 MutS signature motif of the ATPase domain."
Homozygous missense variant in the ATPase domain segregating with POI.
c.118C>T
Homozygous nonsense variant creating a stop codon at residue 40, in an Iranian family with affected siblings of both sexes.
Show evidence (1 reference)
PMID:38175272 SUPPORT Human clinical
"WES analysis of the proband uncovered a novel homozygote nonsense variant, namely c.118C>T in MSH4. This variant resulted in the occurrence of a premature stop codon in residue 40 of MSH4."
Early truncating MSH4 allele.
c.2220_2223del (p.M740fs) with p.T792A
Compound heterozygous genotype in a woman with menarche at 19 and POI diagnosed at 31, with the two alleles inherited from different parents.
Show evidence (1 reference)
PMID:36793102 SUPPORT Human clinical
"A compound heterozygous variant in MSH4 (p.M740fs and p.T792A) was identified in POI-63, who had spontaneous menarche at 19 years of age and diagnosed with POI at 31 years old. The compound heterozygous variant was confirmed to be inherited paternally and maternally, respectively"
Biallelic MSH4 variants in trans in a POI patient, with young adult onset.
💊

Medical Actions

1
Hormone replacement therapy
Action: Hormone Replacement TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hormone Replacement Therapy (NCIT:C15599). NCIT:C15599 is a clinical intervention from the NCI Thesaurus. NCIT:C15599
Agent: estradiol CHEBI:23965 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses estradiol (CHEBI:23965). CHEBI:23965 is a therapeutic agent from Chemical Entities of Biological Interest. progesterone CHEBI:17026 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses progesterone (CHEBI:17026). CHEBI:17026 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
There is no MSH4-directed therapy. As for other causes of POI, estrogen with progestogen replaces ovarian hormones to limit the bone, cardiovascular and other consequences of early estrogen loss; it does not restore fertility, for which donor oocytes are the usual option. The progestogen is bound as progesterone because the ChEBI progestogen class is a role term that the agent slot does not admit; other progestogens are equally used.
Target Phenotypes: Premature ovarian insufficiency HP:0008209 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Premature ovarian insufficiency (HP:0008209). HP:0008209 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39652037 SUPPORT REVIEW SYNTHESIS Human clinical
"Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI."
The 2024 ESHRE POI guideline; applies to POI of any cause, not tested specifically in MSH4-related disease.
🔬

Diagnosis

1
Exome or POI gene panel sequencing
Biallelic MSH4 variants have been found by exome sequencing or POI gene panels; there is no biochemical test specific to the cause.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28541421 SUPPORT Human clinical
"Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4)."
The founding family was solved by exome sequencing.
🐁

Animal Models

1
Msh4 knockout mouse
Targeted disruption of Msh4 causes sterility of both sexes with failed homolog pairing and synapsis in meiotic prophase I.
Species
Mouse
Genotype
Msh4-/-
Publication
PMID:10809667
Pathograph links
Defective Homolog Synapsis and Meiotic Recombination recapitulates fidelity: high Null mice show the meiotic pairing defect expected from the human loss-of-function alleles.
Show evidence (1 reference)
PMID:10809667 SUPPORT Model organism
"Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure."
Msh4-null mice are sterile from meiotic failure in both sexes.
Meiotic Arrest and Germ Cell Loss recapitulates fidelity: high Unpaired oocytes undergo apoptosis shortly after birth.
Show evidence (1 reference)
PMID:10809667 SUPPORT Model organism
"The failure of pairing in these oocytes correlated with an induction of apoptosis, resulting in the almost complete obliteration of germ cell numbers within the ovaries of Msh4−/− females by day 4 pp"
Oocyte apoptosis in female knockout mice.
Ovarian Follicle Depletion partially recapitulates fidelity: moderate Female knockouts lose the oocyte pool and then the ovary itself.
Limitations: The mouse loses nearly all oocytes within days of birth and has no adult ovarian structure, whereas affected women usually have a spontaneous menarche and lose ovarian function in young adulthood. The authors describe this ovarian dysgenesis as specific to Msh4 and Msh5 knockout mice.
Divergences from the human mechanism
species mismatch qualifying
Mouse oocytes are lost perinatally, so the model cannot show the years of residual ovarian function seen in women before POI.
Show evidence (1 reference)
PMID:10809667 SUPPORT Model organism
"Such ovarian dysgenesis after germ cell loss is specific to mice lacking MSH5 and MSH4, as other mutations that result in germ cell depletion do not give rise to such a severe alteration in ovarian development."
The authors note the mouse ovarian phenotype is unusually severe.
{ }

Source YAML

click to show 
name: Premature Ovarian Failure 20
creation_date: "2026-10-19T21:06:18Z"
category: Mendelian
synonyms:
- POF20
- MSH4-related primary ovarian insufficiency
- MSH4-related premature ovarian insufficiency
description: >-
  Premature ovarian failure 20 (POF20; OMIM 619938) is an autosomal recessive
  form of primary ovarian insufficiency caused by biallelic loss-of-function
  variants in MSH4 (MutS homolog 4). MSH4 is a meiosis-specific MutS homolog
  that heterodimerizes with MSH5 to form the MutS-gamma complex, which binds and
  stabilizes recombination intermediates during meiotic prophase I, promotes
  homologous chromosome synapsis, and acts with MLH1 at sites that mature into
  crossovers. Reported pathogenic alleles are splice-site, nonsense, frameshift,
  and missense variants, several of which remove or perturb the conserved
  C-terminal ATPase domain (Walker B motif and MutS signature). Biallelic loss
  is thought to cause oocyte meiotic failure and depletion of the ovarian
  follicle pool, presenting as amenorrhea (most often secondary) and
  infertility in 46,XX individuals; milder presentations with diminished
  ovarian reserve and poor oocyte quality have also been reported. Affected
  brothers in the same families have non-obstructive azoospermia with meiotic
  arrest, which MONDO classifies separately as spermatogenic failure 2.
disease_term:
  preferred_term: premature ovarian failure 20
  term:
    id: MONDO:0030975
    label: premature ovarian failure 20
parents:
- Primary Ovarian Insufficiency
- Meiotic Disorder
notes: >-
  Scope: this entry covers the 46,XX ovarian phenotype of biallelic MSH4
  variants, matching MONDO:0030975. The 46,XY phenotype of the same genotype,
  non-obstructive azoospermia with meiotic arrest, is spermatogenic failure 2
  (MONDO:0007161), which is a separate stub in the curation queue and is not
  lumped here. Several families segregate both phenotypes, so the two entries
  share a mechanism (the meiotic_prophase_failure module) and differ in the
  gonadal consequence. A POI patient carrying one heterozygous variant in each
  of MSH4 and MSH5 has been reported (PMID:36793102); that digenic genotype is
  not part of this recessive entry. No POF20-specific prevalence figure was
  found; MSH4 contributes a small fraction of genetically solved POI.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry homozygous or compound-heterozygous MSH4
    variants; heterozygous parents are unaffected.
  evidence:
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing of members of a Colombian family affected by POI
      allowed us to identify a novel homozygous donor splice-site mutation in
      the meiotic gene MSH4 (MutS Homolog 4). The variant followed a strict
      mendelian segregation within the family
    explanation: >-
      Homozygous MSH4 variant segregating with POI in the founding family.
  - reference: PMID:38175272
    reference_title: "A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was also observed that all affected members had homozygous mutations,
      while their parents were heterozygous and the fertile sister had no
      mutant allele, corresponding to autosomal recessive inheritance.
    explanation: >-
      Segregation of a homozygous MSH4 nonsense variant with gonadal failure,
      with unaffected heterozygous parents.
genetic:
- name: MSH4
  gene_term:
    preferred_term: MSH4
    term:
      id: hgnc:7327
      label: MSH4
  association: Causal
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic loss-of-function MSH4 variants. Reported alleles include a donor
    splice-site variant that skips exon 17 and deletes the Walker B motif
    (p.Ile743_Lys785del), the missense p.Ser754Leu in the MutS signature motif,
    the nonsense c.118C>T at residue 40, and the frameshift c.2220_2223del
    found in trans with p.Thr792Ala (PMID:36793102, which names it p.M740fs)
    or with the nonsense p.Arg910Ter. PMID:37620942 reports what appears to
    be the same four-base deletion as c.2222_2225delAAGA (p.Lys741Argfs*2),
    also with p.Thr792Ala; the two names are kept as the sources give them.
  evidence:
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study describes the first MSH4 mutation associated with POI and
      increases the number of meiotic/DNA repair genes formally implicated as
      being responsible for this condition.
    explanation: >-
      First report establishing MSH4 as a POI gene.
  - reference: PMID:42386447
    reference_title: "MSH4 and MSH5 variants in premature ovarian insufficiency: A literature review and case study."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic MSH4 variants are well-established causes of POI and
      non-obstructive azoospermia (NOA), with MSH4 recognised as a
      high-evidence gene on clinical panels.
    explanation: >-
      Review summarizing the accumulated case evidence that biallelic MSH4
      variants cause POI.
  - reference: PMID:36099812
    reference_title: "Genetic landscape of a large cohort of Primary Ovarian Insufficiency: New genes and pathways and implications for personalized medicine."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A,
      BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in
      isolated patients/families.
    explanation: >-
      A large POI cohort independently confirms MSH4 as a POI gene.
  - reference: PMID:36373164
    reference_title: "Genetic screening in patients with ovarian dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The splice-site variants in SYCE1 and MSH4 affected canonical splicing
      isoforms, leading to missing protein domains or premature termination.
    explanation: >-
      An independent family with an MSH4 splice-site variant in an ovarian
      dysfunction exome cohort.
  variants:
  - name: Exon 17 donor splice-site variant (p.Ile743_Lys785del)
    description: >-
      Homozygous donor splice-site variant in a Colombian family; exon 17
      skipping removes the Walker B motif of the ATPase domain.
    evidence:
    - reference: PMID:28541421
      reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Exon trapping experiments showed that the splice-site mutation induced
        skipping of exon 17. At the protein level, the mutation
        p.Ile743_Lys785del is predicted to lead to the ablation of the highly
        conserved Walker B motif of the ATP-binding domain, thus inactivating
        MSH4.
      explanation: >-
        Functional splicing assay showing loss of the Walker B motif.
  - name: p.Ser754Leu
    description: >-
      Homozygous missense in the MutS signature motif adjacent to the Walker B
      motif, found in a consanguineous Iranian family with both POI and NOA.
    evidence:
    - reference: PMID:33448284
      reference_title: "Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with primary ovarian insufficiency (POI) and non-obstructive
        azoospermia (NOA) were homozygous for the rare missense variant p.
        S754L located in the highly conserved MSH4 MutS signature motif of the
        ATPase domain.
      explanation: >-
        Homozygous missense variant in the ATPase domain segregating with POI.
  - name: c.118C>T
    description: >-
      Homozygous nonsense variant creating a stop codon at residue 40, in an
      Iranian family with affected siblings of both sexes.
    evidence:
    - reference: PMID:38175272
      reference_title: "A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        WES analysis of the proband uncovered a novel homozygote nonsense
        variant, namely c.118C>T in MSH4. This variant resulted in the
        occurrence of a premature stop codon in residue 40 of MSH4.
      explanation: >-
        Early truncating MSH4 allele.
  - name: c.2220_2223del (p.M740fs) with p.T792A
    description: >-
      Compound heterozygous genotype in a woman with menarche at 19 and POI
      diagnosed at 31, with the two alleles inherited from different parents.
    evidence:
    - reference: PMID:36793102
      reference_title: "Next-generation sequencing of 500 POI patients identified novel responsible monogenic and oligogenic variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A compound heterozygous variant in MSH4 (p.M740fs and p.T792A) was
        identified in POI-63, who had spontaneous menarche at 19 years of age
        and diagnosed with POI at 31 years old. The compound heterozygous
        variant was confirmed to be inherited paternally and maternally,
        respectively
      explanation: >-
        Biallelic MSH4 variants in trans in a POI patient, with young adult
        onset.
pathophysiology:
- name: MSH4 Loss of Function
  description: >-
    Biallelic MSH4 variants remove or disrupt the MSH4 protein, most often in
    its C-terminal ATPase domain, inactivating the MSH4-MSH5 (MutS-gamma)
    heterodimer that recognizes and stabilizes Holliday junction recombination
    intermediates in meiotic prophase I.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: MSH4
    term:
      id: hgnc:7327
      label: MSH4
  molecular_functions:
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Exon trapping experiments showed that the splice-site mutation induced
      skipping of exon 17.
    explanation: >-
      Splicing assay of the founding allele; the resulting in-frame deletion
      removes the Walker B ATPase motif, which the authors predict
      inactivates MSH4.
  - reference: PMID:33448284
    reference_title: "Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Along with its heterodimer partner MSH5, it is responsible for
      double-strand Holliday junction recognition and stabilization, to ensure
      accurate chromosome segregation during meiosis.
    explanation: >-
      States the normal MutS-gamma function that the disease alleles remove.
  - reference: PMID:30467025
    reference_title: "MutS\u03B3-Induced DNA Conformational Changes Provide Insights into Its Role in Meiotic Recombination."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Similar to the human protein, Sc Msh4-Msh5 exhibits the highest affinity
      for the HJ with a Kd < 0.4 nM in solution.
    explanation: >-
      Purified yeast MutS-gamma binds Holliday junctions most tightly, as the
      human complex does; the structural role is inferred for human MSH4.
  downstream:
  - target: Defective Homolog Synapsis and Meiotic Recombination
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10809667
      reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Although meiosis is initiated in Msh4 mutant male and female mice, as
        indicated by the chromosomal localization of RAD51 and COR1 during
        leptonema/zygonema, the chromosomes fail to undergo normal pairing.
      explanation: >-
        Loss of Msh4 in mice prevents normal homolog pairing after meiotic
        entry.
- name: Defective Homolog Synapsis and Meiotic Recombination
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  description: >-
    Without MutS-gamma, homologous chromosomes fail to pair and synapse
    normally, and recombination intermediates are not channelled into
    MLH1-marked crossovers.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: homologous chromosome pairing at meiosis
    term:
      id: GO:0007129
      label: homologous chromosome pairing at meiosis
    modifier: DECREASED
  - preferred_term: synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  - preferred_term: reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:10809667
    reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results show that MSH4 localization on chromosomes during the early
      stages of meiosis is essential for normal chromosome synapsis in prophase
      I and that it acts in the same pathway as MSH5.
    explanation: >-
      Mouse genetics place MSH4 upstream of synapsis, in the MSH5 pathway.
  - reference: PMID:10928988
    reference_title: "MSH4 acts in conjunction with MLH1 during mammalian meiosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results suggest that MSH4 is first required for chromosome synapsis
      and that this MutS homologue is involved later with MLH1 in meiotic
      reciprocal recombination.
    explanation: >-
      MSH4 interacts with MLH1 and colocalizes with it on synaptonemal
      complexes, linking MSH4 to crossover formation.
  downstream:
  - target: Meiotic Arrest and Germ Cell Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34755185
      reference_title: "Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        γH2AX staining revealed an arrest in early prophase of meiosis I in
        individuals with pathogenic MSH4 or MSH5 variants.
      explanation: >-
        Testicular tissue from human MSH4-variant carriers shows arrest in
        early meiotic prophase I. Fetal ovarian tissue is not accessible to the
        same analysis, so the oocyte arrest is inferred from this male finding
        and from the mouse.
- name: Meiotic Arrest and Germ Cell Loss
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Germ cells that cannot complete synapsis and recombination arrest in
    meiotic prophase I and are eliminated, so functional gametes are not
    produced in either sex.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:10809667
    reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Disruption of the Msh4 gene in mice results in male and female sterility
      due to meiotic failure.
    explanation: >-
      Msh4-null mice of both sexes are sterile from meiotic failure.
  - reference: PMID:10809667
    reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The failure of pairing in these oocytes correlated with an induction of
      apoptosis, resulting in the almost complete obliteration of germ cell
      numbers within the ovaries of Msh4−/− females by day 4 pp
    explanation: >-
      In female knockout mice, unpaired oocytes undergo apoptosis and are
      almost all lost within days of birth.
  downstream:
  - target: Ovarian Follicle Depletion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10809667
      reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        As in the case of Msh5−/− females, the loss of the oocyte pool resulted
        in the disruption of ovarian development and the complete loss of
        ovarian structures in the adult Msh4−/− female.
      explanation: >-
        Oocyte loss leads to loss of ovarian structures in the mouse.
- name: Ovarian Follicle Depletion
  conforms_to: "meiotic_prophase_failure#Ovarian Follicle Depletion and Primary Ovarian Insufficiency"
  description: >-
    Loss of oocytes depletes the ovarian follicle pool. Depending on residual
    reserve, women present with amenorrhea and premature ovarian insufficiency,
    or with diminished ovarian reserve and poor oocyte yield and quality in
    assisted reproduction.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: female gamete generation
    term:
      id: GO:0007292
      label: female gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:37620942
    reference_title: "Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings indicate a correlation between MSH4 variants and reduced
      oocyte quality, as well as abnormal morphology of the first polar body,
      thereby expanding the phenotypic spectrum associated with MSH4 variants.
    explanation: >-
      A compound-heterozygous patient with diminished ovarian reserve had poor
      oocyte quantity and quality, the milder end of follicle depletion.
  - reference: PMID:10809667
    reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As in the case of Msh5−/− females, the loss of the oocyte pool resulted
      in the disruption of ovarian development and the complete loss of
      ovarian structures in the adult Msh4−/− female.
    explanation: >-
      The mouse shows the extreme of follicle depletion, with no adult ovary.
  downstream:
  - target: Premature ovarian insufficiency
    causal_link_type: DIRECT
  - target: Secondary amenorrhea
    causal_link_type: DIRECT
  - target: Female infertility
    causal_link_type: DIRECT
  - target: Elevated circulating follicle stimulating hormone level
    causal_link_type: DIRECT
    description: >-
      Loss of follicles removes ovarian negative feedback on the pituitary.
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Cessation of ovarian function before age 40 is the defining feature in
    46,XX carriers of biallelic MSH4 variants.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
    onset:
      onset_category: YOUNG_ADULT
      notes: >-
        Reported cases present after a spontaneous menarche, for example POI
        diagnosed at 31 after menarche at 19 (PMID:36793102).
  evidence:
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study describes the first MSH4 mutation associated with POI
    explanation: >-
      POI in the founding homozygous family.
  - reference: PMID:33448284
    reference_title: "Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with primary ovarian insufficiency (POI) and non-obstructive
      azoospermia (NOA) were homozygous for the rare missense variant p.
      S754L
    explanation: >-
      POI in an independent homozygous family.
  - reference: PMID:34755185
    reference_title: "Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, we detected biallelic variants in MSH4 in two men with MeiA
      and in the sister of one proband with POI.
    explanation: >-
      POI in the sister of an MSH4-variant man with meiotic arrest.
- name: Elevated circulating follicle stimulating hormone level
  category: Endocrine
  description: >-
    Raised FSH is the laboratory finding that defines POI; it is also raised
    in the milder diminished ovarian reserve presentation.
  phenotype_term:
    preferred_term: Elevated circulating follicle stimulating hormone level
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  evidence:
  - reference: PMID:37620942
    reference_title: "Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The basic hormone levels of the proband were as follows:
      follicle-stimulating hormone (FSH), 29.86 mIU/mL
    explanation: >-
      FSH well above the 3-12 mIU/mL normal range the same paper gives, in a
      woman with biallelic MSH4 variants.
  - reference: PMID:37620942
    reference_title: "Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Normal range of AFC: 7–20; Follicle-stimulating hormone: 3–12 mIU/mL
    explanation: >-
      Reference range the authors used to flag the FSH value as abnormal.
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by an early cessation of menses and high FSH levels
    explanation: >-
      Defines POI by high FSH in the paper that reported the founding MSH4
      family.
- name: Secondary amenorrhea
  category: Reproductive
  description: >-
    Most affected women have menarche followed by loss of menses.
  phenotype_term:
    preferred_term: Secondary amenorrhea
    term:
      id: HP:0000869
      label: Secondary amenorrhea
  evidence:
  - reference: PMID:42386447
    reference_title: "MSH4 and MSH5 variants in premature ovarian insufficiency: A literature review and case study."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals predominantly present with secondary amenorrhoea,
      with emerging evidence for milder phenotypes, including diminished
      ovarian reserve (DOR).
    explanation: >-
      Literature review of MSH4/MSH5 POI cases; the review pools MSH4 and MSH5
      patients.
- name: Female infertility
  category: Reproductive
  description: >-
    Infertility, including failed in vitro fertilization from poor oocyte
    quantity and quality.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:37620942
    reference_title: "Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with poor oocyte quantity and quality, resulting
      in unsuccessful in vitro fertilization cycles.
    explanation: >-
      Infertility with failed IVF in a woman with biallelic MSH4 variants.
  - reference: PMID:38175272
    reference_title: "A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results show that the testicular sperm retrieval and ovarian
      stimulation cycles have not been successful yet.
    explanation: >-
      Review of reported MSH4 cases notes unsuccessful ovarian stimulation.
diagnosis:
- name: Exome or POI gene panel sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Biallelic MSH4 variants have been found by exome sequencing or POI gene
    panels; there is no biochemical test specific to the cause.
  evidence:
  - reference: PMID:28541421
    reference_title: "A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing of members of a Colombian family affected by POI
      allowed us to identify a novel homozygous donor splice-site mutation in
      the meiotic gene MSH4 (MutS Homolog 4).
    explanation: >-
      The founding family was solved by exome sequencing.
treatments:
- name: Hormone replacement therapy
  description: >-
    There is no MSH4-directed therapy. As for other causes of POI, estrogen
    with progestogen replaces ovarian hormones to limit the bone,
    cardiovascular and other consequences of early estrogen loss; it does not
    restore fertility, for which donor oocytes are the usual option. The
    progestogen is bound as progesterone because the ChEBI progestogen class
    is a role term that the agent slot does not admit; other progestogens are
    equally used.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
    - preferred_term: progesterone
      term:
        id: CHEBI:17026
        label: progesterone
  target_phenotypes:
  - preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:39652037
    reference_title: "Evidence-based guideline: Premature Ovarian Insufficiency."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although hormone therapy (HT) can mitigate some of these effects, many
      questions still remain regarding the optimal management of POI.
    explanation: >-
      The 2024 ESHRE POI guideline; applies to POI of any cause, not tested
      specifically in MSH4-related disease.
animal_models:
- name: Msh4 knockout mouse
  species: Mouse
  genotype: Msh4-/-
  publication: PMID:10809667
  description: >-
    Targeted disruption of Msh4 causes sterility of both sexes with failed
    homolog pairing and synapsis in meiotic prophase I.
  modeled_mechanisms:
  - target: Defective Homolog Synapsis and Meiotic Recombination
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Null mice show the meiotic pairing defect expected from the human
      loss-of-function alleles.
    evidence:
    - reference: PMID:10809667
      reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Disruption of the Msh4 gene in mice results in male and female
        sterility due to meiotic failure.
      explanation: >-
        Msh4-null mice are sterile from meiotic failure in both sexes.
  - target: Meiotic Arrest and Germ Cell Loss
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Unpaired oocytes undergo apoptosis shortly after birth.
    evidence:
    - reference: PMID:10809667
      reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The failure of pairing in these oocytes correlated with an induction of
        apoptosis, resulting in the almost complete obliteration of germ cell
        numbers within the ovaries of Msh4−/− females by day 4 pp
      explanation: >-
        Oocyte apoptosis in female knockout mice.
  - target: Ovarian Follicle Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Female knockouts lose the oocyte pool and then the ovary itself.
    limitations: >-
      The mouse loses nearly all oocytes within days of birth and has no adult
      ovarian structure, whereas affected women usually have a spontaneous
      menarche and lose ovarian function in young adulthood. The authors
      describe this ovarian dysgenesis as specific to Msh4 and Msh5 knockout
      mice.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse oocytes are lost perinatally, so the model cannot show the
        years of residual ovarian function seen in women before POI.
    evidence:
    - reference: PMID:10809667
      reference_title: "MutS homolog 4 localization to meiotic chromosomes is required for chromosome pairing during meiosis in male and female mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Such ovarian dysgenesis after germ cell loss is specific to mice
        lacking MSH5 and MSH4, as other mutations that result in germ cell
        depletion do not give rise to such a severe alteration in ovarian
        development.
      explanation: >-
        The authors note the mouse ovarian phenotype is unusually severe.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Premature Ovarian Failure 20 (MSH4) · 2026-10-19T21:06:18Z · View source

New entry for premature ovarian failure 20 (MONDO:0030975; OMIM 619938; MSH4). Entry type DISEASE. Scoped to the 46,XX ovarian phenotype; the male phenotype of the same genotype is spermatogenic failure 2 (MONDO:0007161), a separate stub. Pathophysiology conforms to three nodes of the meiotic_prophase_failure module. Deep research: one openscientist report. The run exited 3 on a read timeout resolving MedGen:1808256 and the report landed with no validation record (issue #11896). Reference validation was restored with just validate-research-reference (18/18 resolved); validate-research-terms failed again on the same CURIE, so term validation was run with --skip-prefix MedGen added, as documented in #11896. Term validation flagged three mislabelled NCIT treatment codes in the report (NCIT:C62002 is Amiodarone, NCIT:C713 is Oligonucleotide, NCIT:C92755 is Chorionic Villus Sampling); none was used, and HRT is bound to NCIT:C15599 from the term cache. just preflight-dr WARN: MSH5 is mentioned at 25% of MSH4; those sections describe the MutS-gamma partner and digenic MSH4+MSH5 cases, not a different disease. The report's statement that the index family was consanguineous is not in the cited abstract and was not used. An OMIM number written from memory in the first draft (618315) was corrected to 619938, the xref MONDO records. Not used: generic POI epidemiology and HRT outcome papers (PMID:39448037, PMID:20938225, PMID:40377060, PMID:40620015, PMID:40936058), MutL-gamma biochemistry (PMID:40319035, PMID:32814904), and MCM8 papers (PMID:25873734, PMID:32048466). Validation: just validate, validate-terms, count-verified-snippets (all verified), check-entity-refs pass.

OpenScientist ▸
Key Findings
openscientist-autonomous 18 citations 2026-10-19T21:01:24.975054

Key Findings

Finding 1 — POF20 is caused by biallelic loss-of-function variants in MSH4 and is inherited autosomal-recessively [H]

POF20 maps unambiguously to the identifier set OMIM:619938 / MONDO:0030975 / UMLS:C5677011 / GARD:0025670. The Monarch Initiative records a Causal-Gene-to-Disease association linking HGNC:7327 (MSH4) to POF20 with autosomal recessive inheritance (HP:0000007). The disease was first described by Carlosama et al. (2017), who used whole-exome sequencing in a consanguineous Colombian family to identify a homozygous donor splice-site mutation causing skipping of exon 17 (p.Ile743_Lys785del). The variant segregated with POI and was absent in 135 fertile controls.

"Whole-exome sequencing of members of a Colombian family affected by POI allowed us to identify a novel homozygous donor splice-site mutation in the meiotic gene MSH4 (MutS Homolog 4)." — PMID: 28541421

"Our study describes the first MSH4 mutation associated with POI." — PMID: 28541421

Multiple independent biallelic variants have since confirmed the association, including reports from large POI gene-panel and exome cohorts PMID: 36099812, PMID: 36793102, PMID: 36373164, and PMID: 38175272.

Note on causal-gene correction: Early in this investigation the gene was provisionally listed as MCM8. This was corrected to MSH4, which is the gene formally linked to OMIM 619938 / POF20. MCM8 defects cause a distinct POI entity (POF10 / OMIM 612885 — see PMID: 25873734, PMID: 32048466).

Finding 2 — Mechanism: MSH4 loss disrupts the MutSγ (MSH4–MSH5) complex, abolishing meiotic crossovers [V/H]

MSH4 heterodimerizes with MSH5 to form MutSγ, which binds and stabilizes Holliday-junction (HJ) recombination intermediates with the highest affinity among tested substrates (nanomolar K_d) PMID: 30467025. MutSγ licenses the MLH1–MLH3 (MutLγ) endonuclease, acting with EXO1 and RFC-PCNA, to resolve double Holliday junctions into crossovers PMID: 40319035, PMID: 32814904. Pathogenic MSH4 variants are typically loss-of-function or disrupt the conserved C-terminal ATPase/Walker-B domain.

"MSH4 and MSH5 encode components of the MutSγ complex, which stabilises Holliday junctions during meiotic recombination." — PMID: 42386447

"Pathogenic variants are typically loss-of-function and/or disrupt conserved functional domains essential for meiotic recombination, in particular the C-terminal ATPase domain found in both MSH4 and MSH5." — PMID: 42386447

"The endonuclease activity of MLH1-MLH3 (MutLγ) is stimulated by MSH4-MSH5 (MutSγ), EXO1, and RFC-PCNA to resolve meiotic recombination intermediates such as double Holliday junctions (HJs) into crossovers." — PMID: 40319035

Loss of crossovers causes failure of homolog pairing/synapsis, meiotic arrest, apoptotic loss of oocytes, and streak/dysgenetic ovaries.

Finding 3 — Msh4-null mice recapitulate POF20; the mechanism is sex-shared (POI in females, azoospermia in males) [M/H]

Msh4-knockout mice are sterile in both sexes due to meiotic failure, with defective chromosome pairing/synapsis in prophase I. MSH4 acts in the same genetic pathway as MSH5.

"Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure." — PMID: 10809667

"MSH4 localization on chromosomes during the early stages of meiosis is essential for normal chromosome synapsis in prophase I and that it acts in the same pathway as MSH5." — PMID: 10809667

In humans, the identical biallelic MSH4 defect produces POI in women and non-obstructive azoospermia (NOA) in their brothers within the same family, reflecting the shared meiosis-I requirement.

"inherited defects in meiosis I may result in common causes for both POI and NOA." — PMID: 38175272

Finding 4 — MSH4 is loss-of-function-tolerant in heterozygotes, consistent with the recessive mechanism [C]

gnomAD v2 constraint metrics for MSH4 (ENSG00000057468) show it is not depleted for predicted loss-of-function variants: pLI ≈ 0 (7.8 × 10⁻³⁴), observed/expected LoF (oe_lof) = 0.93 (90% CI 0.80–1.10; LOEUF ≈ 1.10), obs_lof = 106 vs exp_lof = 113.7, lof_z = 0.61. Heterozygous LoF is therefore well tolerated — exactly what is expected for a gene that causes disease only when biallelically inactivated.

ClinVar lists 207 MSH4 records, of which 45 are classified pathogenic and 14 likely pathogenic. Reported pathogenic variant classes include canonical splice-site (exon-17 skipping; p.Ile743_Lys785del), nonsense (c.118C>T, p.Gln40*), frameshift, and missense affecting the conserved C-terminal ATPase/Walker-B domain.

"the mutation p.Ile743_Lys785del is predicted to lead to the ablation of the highly conserved Walker B motif of the ATP-binding domain, thus inactivating MSH4." — PMID: 28541421

Finding 5 — Clinical phenotype: young-adult-onset secondary amenorrhea, infertility, hypergonadotropic hypogonadism [H]

Official HPO/OMIM annotations for OMIM:619938 (all from the index family, frequency 2/2 = 100%) are: Young adult onset (HP:0011462); Secondary amenorrhea (HP:0000869); Female infertility (HP:0008222); Elevated circulating FSH (HP:0008232); Elevated circulating LH (HP:0011969); Autosomal recessive inheritance (HP:0000007).

"characterized by an early cessation of menses and high FSH levels." — PMID: 28541421

Broader literature indicates affected women predominantly present with secondary amenorrhea (often after initially normal menarche/puberty), with a phenotypic spectrum extending to primary amenorrhea at the severe end and milder diminished ovarian reserve (DOR) at the mild end.

"Affected individuals predominantly present with secondary amenorrhoea, with emerging evidence for milder phenotypes, including diminished ovarian reserve (DOR)." — PMID: 42386447

Finding 6 — MSH4 is deeply conserved; functional models span yeast, worm, zebrafish, and mouse [M/C]

MSH4 orthologs exist across eukaryotes: mouse Msh4 (Gene 55993), rat (295541), zebrafish msh4 (559917), chicken (424725), dog (612681), cow (616664), chimpanzee (469357), macaque (705294), S. cerevisiae MSH4 (850545), C. elegans him-14/msh-4 (174157), and Arabidopsis thaliana MSH4 (827450). The mouse knockout validates the model.

"Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure." — PMID: 10809667

Finding 7 — Prognosis and management: non-progressive lifelong infertility with estrogen-deprivation sequelae; HRT + donor-oocyte IVF [H]

POF20 is not life-threatening but causes irreversible hypergonadotropic hypogonadism. Untreated premature estrogen deficiency increases risks of osteoporosis/fracture, cardiovascular disease, adverse cognitive and sexual-health outcomes, and all-cause mortality.

"Premature ovarian insufficiency can result in long-term decrements to all-cause mortality, bone density, cardiovascular health, sexual health, cognitive health, and body mass. Hormone replacement therapy has been demonstrated to reverse these long-term sequalae." — PMID: 39448037

Management follows the 2024 ESHRE/ASRM/IMS evidence-based POI guideline.

"The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae and treatment of POI." — PMID: 39652037

Finding 8 — Investigation complete: comprehensive 15-section characterization with corrected causal gene [C]

The verified identifier set and ontology annotations (below) anchor a complete 15-section characterization. MSH4 aliases POF20 and SPGF2 (the male spermatogenic-failure counterpart) were confirmed via mygene.info, and the Monarch Causal-Gene-to-Disease association (MSH4 → POF20, autosomal recessive) was verified.

Mechanistic Model / Interpretation

Causal chain — from mutation to clinical manifestation

1. Biallelic LoF variant in MSH4 (splice / nonsense / frameshift / ATPase-domain missense)
│  results in
▼
2. Absent or non-functional MSH4 protein  →  cannot heterodimerize with MSH5
│  leads to
▼
3. Loss of the MutSγ (MSH4–MSH5) complex  →  Holliday junctions not stabilized   [inferred: biochemistry]
│  results in
▼
4. MLH1–MLH3 (MutLγ) resolvase not licensed  →  double Holliday junctions not resolved   [inferred: biochemistry]
│  leads to
▼
5. Meiotic crossovers fail to form  →  homologous chromosomes do not pair/synapse   [demonstrated: mouse]
│  results in
▼
6. Meiosis-I arrest  →  apoptotic elimination of germ cells / oocytes   [inferred from model/comparative]
│  leads to
▼
7. Depletion of the ovarian follicle pool  →  streak/dysgenetic ovaries
│  results in
▼
8. Hypergonadotropic hypogonadism (loss of estradiol/inhibin feedback → ↑FSH, ↑LH)
│  manifests as
▼
9. CLINICAL: young-adult secondary amenorrhea + female infertility (POF20)

   ── BRANCH (same genotype, male relatives) ──
7b. Spermatogenic meiotic arrest → non-obstructive azoospermia (SPGF2)

Steps 3–4 are inferred from biochemical and model-organism data (yeast MutSγ binding assays, mouse knockout synapsis defects) rather than demonstrated directly in human ovary. Steps 1, 2, 8, and 9 are established in human patients.

Upstream vs downstream

Position Event Evidence type
Upstream (initiating) Biallelic MSH4 LoF Human genetics (PMID 28541421)
Upstream MutSγ complex loss Biochemistry (PMID 30467025)
Midstream Crossover failure, synapsis failure Mouse model (PMID 10809667)
Downstream Oocyte apoptosis, follicle depletion Inferred / comparative
Downstream (clinical) Hypergonadotropic hypogonadism, amenorrhea, infertility Human clinical (PMID 28541421)

Ontology annotation set

Category Terms
Disease MONDO:0030975; OMIM:619938; UMLS:C5677011; MedGen:1808256; GARD:0025670
Gene/Protein HGNC:7327 (MSH4); NCBI 4438; Ensembl ENSG00000057468; UniProt O15457
Phenotype (HPO) HP:0000869 (secondary amenorrhea); HP:0008222 (female infertility); HP:0008232 (elevated FSH); HP:0011969 (elevated LH); HP:0011462 (young adult onset); HP:0000815 (hypergonadotropic hypogonadism); HP:0008209 (premature ovarian insufficiency); HP:0000786 (amenorrhea); HP:0000007 (AR inheritance)
Biological process (GO) GO:0007131 (reciprocal meiotic recombination); GO:0007127 (meiosis I); GO:0006298 (mismatch repair)
Cellular component (GO) GO:0000795 (synaptonemal complex); GO:0005713 (recombination nodule); GO:0005634 (nucleus); GO:0000794 (condensed nuclear chromosome)
Molecular function (GO) GO:0005524 (ATP binding); GO:0030983 (mismatched DNA binding); GO:0140664 (ATP-dependent DNA damage sensor activity); GO:0003690 (dsDNA binding)
Anatomy (UBERON) UBERON:0000992 (ovary)
Cell type (CL) CL:0000023 (oocyte); CL:0000020 (spermatogonium) / CL:0000019 (sperm) in males
Treatment (NCIT) NCIT:C62002 (HRT); NCIT:C617 (estrogen); NCIT:C713 (progestin); NCIT:C15354 (IVF); NCIT:C92755 (oocyte donation)

Section-by-Section Report

1. Disease Information

POF20 is a rare monogenic form of primary/premature ovarian insufficiency (POI) — loss of normal ovarian function before age 40 — defined by its causal gene MSH4. Key identifiers: OMIM 619938, MONDO:0030975, UMLS C5677011, MedGen 1808256, GARD 0025670. There is no POF20-specific ICD code; it is captured under POI/premature menopause codes (ICD-10 E28.31, premature ovarian failure; ICD-11 5A80.1) and MeSH Primary Ovarian Insufficiency (D016649). Synonyms/alternative names: Premature Ovarian Failure 20; MSH4-related POI; ovarian insufficiency due to MSH4 deficiency. The male allelic counterpart is Spermatogenic Failure 2 (SPGF2). Information is derived from aggregated disease-level resources (OMIM, Monarch, ClinVar) and a small number of individual-patient reports/case series rather than EHR-scale datasets.

2. Etiology

Causal factor: entirely genetic — biallelic (homozygous or compound heterozygous) loss-of-function variants in MSH4. Genetic risk factors: the only established risk factor is carriage of two pathogenic MSH4 alleles; consanguinity substantially raises risk (the index family was consanguineous Colombian; PMID: 28541421). Digenic/oligogenic contributions have been reported, including digenic MSH4+MSH5 variants PMID: 36793102. Environmental risk factors: none specific to POF20 — this is a Mendelian disease; general POI environmental contributors (chemotherapy, radiation, smoking) are not causal here. Protective factors: none genetic identified; general estrogen-protective lifestyle factors do not modify the underlying meiotic defect. Gene–environment interactions: not established; the phenotype is driven by the germline genotype.

3. Phenotypes

Phenotype HPO term Type Onset Frequency
Secondary amenorrhea HP:0000869 Clinical sign Young adult 2/2 (100%) index family
Female infertility HP:0008222 Clinical Young adult High
Elevated circulating FSH HP:0008232 Lab abnormality Young adult 2/2 (100%)
Elevated circulating LH HP:0011969 Lab abnormality Young adult 2/2 (100%)
Hypergonadotropic hypogonadism HP:0000815 Lab/clinical Young adult High
Premature ovarian insufficiency HP:0008209 Clinical <40 y Defining
Young adult onset HP:0011462 Modifier 16–40 y Typical

Severity is variable (primary amenorrhea → secondary amenorrhea → DOR); the course is stable/non-progressive once ovarian reserve is lost. Quality-of-life impact: substantial — infertility, estrogen-deficiency symptoms (vasomotor, genitourinary, mood), and long-term bone/cardiovascular/cognitive risks; POI broadly impairs QoL and psychological well-being (PMID: 40377060).

4. Genetic / Molecular Information

Causal gene: MSH4 (OMIM 602105; HGNC:7327; locus 1p31.1; chr1:75,796,882–75,913,242, GRCh38; NCBI Gene 4438; UniProt O15457). Variant spectrum: canonical splice-site (exon-17 skipping, p.Ile743_Lys785del — PMID: 28541421); nonsense (c.118C>T, p.Gln40 — PMID: 38175272); frameshift; and missense in the conserved C-terminal ATPase/Walker-B domain (PMID: 42386447). Classification: ClinVar — 45 pathogenic, 14 likely pathogenic of 207 records. Allele frequency: pathogenic alleles are rare/absent in gnomAD; MSH4 is LoF-tolerant in heterozygotes (pLI≈0, LOEUF≈1.10). Origin: germline. Functional consequence: loss of function (recessive). Modifier genes: MSH5 (digenic reports); co-occurring meiotic-gene variants may modulate severity. Epigenetic/chromosomal abnormalities: none specific to POF20 (though POI generally has epigenetic contributors — PMID: 40620015).

5. Environmental Information

Not applicable as a cause — POF20 is monogenic. No toxins, lifestyle factors, or infectious agents are implicated in its etiology. (Environmental/iatrogenic exposures cause other POI subtypes but not MSH4-related disease.)

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the ordered causal chain. In brief: MSH4 LoF → loss of MutSγ (MSH4–MSH5) → failure to stabilize Holliday junctions → failure to license MutLγ (MLH1–MLH3)/EXO1/RFC-PCNA → no crossovers → synapsis/pairing failure → meiosis-I arrest → oocyte apoptosis → follicle depletion → hypergonadotropic hypogonadism → amenorrhea/infertility. Key pathway: meiotic homologous recombination (not Wnt/MAPK/mTOR). Cellular process: apoptosis of germ cells following meiotic arrest. Protein dysfunction: loss of ATPase-dependent HJ-binding function. Cell types: oocytes (CL:0000023); subcellular site: synaptonemal complex (GO:0000795). Male branch → spermatocyte arrest → azoospermia.

7. Anatomical Structures Affected

Primary organ: ovary (UBERON:0000992), typically streak/dysgenetic. Body system: endocrine/reproductive (hypothalamic-pituitary-ovarian axis). Secondary involvement (from estrogen deficiency): skeleton (osteoporosis), cardiovascular system, CNS (cognition/mood), genitourinary tissues. Tissue/cell: germ cells — oocytes (CL:0000023); in males, spermatocytes/spermatogonia. Subcellular: nucleus (GO:0005634), synaptonemal complex (GO:0000795), condensed nuclear chromosome (GO:0000794). Lateralization: bilateral ovarian involvement.

8. Temporal Development

Onset: young adult (HP:0011462), typically after apparently normal puberty/menarche; insidious/chronic onset of oligo-/amenorrhea. Progression: the primary defect is developmental (meiotic failure in fetal/early life depletes the oocyte pool); it presents clinically as non-progressive, stable ovarian insufficiency once reserve is exhausted. Disease course: chronic, lifelong. Remission: none spontaneous; sporadic ovulation is rare. Critical period: the meiotic window is prenatal/perinatal — by the time of diagnosis the germ-cell pool is already depleted, limiting fertility-preservation opportunities to early-diagnosed cases.

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007). Penetrance: appears high in biallelic carriers but formally incompletely characterized (small case numbers). Expressivity: variable (primary amenorrhea ↔ DOR). Epidemiology: POI overall affects ~3.5% of women (PMID: 39652037); MSH4/POF20 is a rare monogenic subset — in targeted-panel/exome POI cohorts, MSH4 accounts for a small percentage of solved cases (PMID: 36793102, PMID: 36373164, PMID: 36099812). Consanguinity/founder effects: homozygous cases enriched in consanguineous families. Carrier frequency: low; MSH4 LoF alleles are tolerated in heterozygotes (gnomAD). Sex: females present with POI, males with NOA — same genotype, sex-specific manifestation.

10. Diagnostics

Clinical/lab: elevated FSH (ESHRE 2024: a single FSH >25 IU/L suffices for POI diagnosis), elevated LH, low estradiol, low AMH; pelvic ultrasound shows small ovaries/reduced antral follicle count. Genetic testing: POI gene panels or whole-exome sequencing identify biallelic MSH4 variants — the definitive diagnostic for POF20. WES/panel testing is high-yield in familial/consanguineous POI (PMID: 36099812). Karyotype and FMR1 premutation testing are performed to exclude common POI causes. Differential diagnosis: Turner syndrome, FMR1 premutation, autoimmune oophoritis, other monogenic POI (FOXL2, NOBOX, MCM8/9, MSH5, HFM1, SYCE1, STAG3). Screening: cascade genetic testing of at-risk relatives (including male siblings for azoospermia risk).

11. Outcome / Prognosis

Survival: not directly life-threatening; however untreated POI is associated with increased all-cause mortality and cardiovascular/skeletal morbidity (PMID: 39448037, PMID: 20938225). Morbidity: infertility, osteoporosis/fracture risk, cardiovascular disease, cognitive and sexual-health effects, vasomotor symptoms. Recovery: ovarian function is irreversibly lost; HRT reverses many estrogen-deprivation sequelae but not fertility. Prognostic factors: younger age at ART and milder (DOR) phenotype associate with better reproductive prognosis (PMID: 40936058).

12. Treatment

No disease-modifying/curative therapy exists. Management is supportive and hormonal:

Intervention NCIT Purpose
Hormone replacement therapy (estradiol + progestogen) NCIT:C62002 Symptom control; bone/CV/cognitive protection until ~age 51
Estrogen NCIT:C617 Core HRT component
Progestin NCIT:C713 Endometrial protection
In vitro fertilization NCIT:C15354 Fertility (with donor oocytes)
Oocyte donation NCIT:C92755 Principal fertility option

Adjuncts: calcium/vitamin D, DXA bone-density monitoring, psychological support (2024 ESHRE/ASRM/IMS guideline, 145 recommendations — PMID: 39652037). Own-oocyte IVF is generally non-viable because meiosis is abolished; donor-oocyte/donor-embryo IVF is the mainstay. No gene therapy or pharmacogenomic strategy is currently applicable.

13. Prevention

Primary prevention is not possible (germline Mendelian disease). Secondary/tertiary prevention: early diagnosis enables timely HRT to prevent osteoporosis and cardiovascular complications, and (if diagnosed before pool exhaustion) consideration of fertility preservation. Genetic counseling is central: autosomal-recessive recurrence risk (25% for future siblings of a proband), carrier testing of partners in consanguineous unions, and counseling of male relatives regarding azoospermia risk. Preimplantation/prenatal genetic testing is feasible for families with a known biallelic genotype.

14. Other Species / Natural Disease

MSH4 is deeply conserved. Orthologs: mouse Msh4 (Gene 55993; taxid 10090), rat (295541), zebrafish msh4 (559917), chicken (424725), dog (612681), cow (616664), chimpanzee (469357), macaque (705294), S. cerevisiae MSH4 (850545; taxid 4932), C. elegans him-14/msh-4 (174157; taxid 6239), Arabidopsis thaliana MSH4 (827450). The meiotic recombination function is conserved from yeast to mammals. No specific naturally occurring companion-animal disease is catalogued for MSH4, but the shared mechanism makes cross-species meiotic sterility phenotypes directly comparable.

15. Model Organisms

Model Type Phenotype recapitulation
Mouse Msh4-null Mammalian knockout Male + female sterility; prophase-I synapsis failure — faithfully recapitulates POF20/SPGF2 (PMID: 10809667)
S. cerevisiae MSH4 Yeast Crossover/recombination defects; biochemistry of MutSγ–HJ binding (PMID: 30467025)
C. elegans him-14/msh-4 Invertebrate Meiotic crossover failure, chromosome missegregation
Zebrafish msh4 Vertebrate Meiotic model (ortholog available)

Model strengths: the mouse knockout captures the core sterility/meiotic-failure phenotype and the sex-shared mechanism. Limitations: rodent ovarian-aging/reserve dynamics differ from humans, and human milder (DOR) phenotypes are harder to model. Resources: MGI, ZFIN, SGD, WormBase.

Evidence Base

PMID Title / focus Role in this report Evidence type
28541421 Homozygous donor splice-site mutation in MSH4 causes POI Foundational — first MSH4–POI link; variant, phenotype, Walker-B ablation Human clinical/genetic
42386447 MSH4 and MSH5 variants in POI: review and case study Variant spectrum (LoF/ATPase); phenotype spectrum (2° amenorrhea → DOR) Review + case
38175272 Homozygous nonsense MSH4 variant → POI and NOA Sex-shared meiosis-I mechanism; nonsense variant Human clinical/genetic
10809667 Msh4 knockout mouse Model organism; synapsis role; same pathway as MSH5 Mouse model
30467025 MutSγ–DNA conformational changes MutSγ binds HJs with nanomolar affinity In vitro biochemistry
40319035 EXO1 promotes MLH1-MLH3 endonuclease MutSγ licenses MutLγ to resolve dHJs into crossovers In vitro/biochemistry
32814904 Regulation of MLH1-MLH3 endonuclease in meiosis Downstream crossover resolution Review/biochemistry
36099812 Genetic landscape of large POI cohort Confirms MSH4 causal role; diagnostic yield Human cohort
36793102 NGS of 500 POI patients Digenic MSH4+MSH5; compound-het confirmation Human cohort
36373164 Genetic screening in ovarian dysfunction MSH4 splice variants; expands spectrum Human cohort
40936058 Genetic variants in DOR/POI & ART outcomes Meiotic variants → poor ART; younger age better Human cohort
39652037 2024 ESHRE/ASRM/IMS POI guideline Diagnosis (FSH>25) and management framework Guideline
39448037 HRT in radiation-induced POI Estrogen-deprivation sequelae; HRT reverses them Review/clinical
20938225 Skeletal effect of natural early menopause Bone/mortality risks of early estrogen loss Review
25873734 MCM8 mutations → gonadal failure Distinguishes POF10 (MCM8) from POF20 (MSH4) Human genetic

Consistency: All independent lines of evidence — human genetics (multiple families/cohorts), the mouse knockout, and yeast/worm biochemistry — converge on a single coherent model: MSH4 LoF → MutSγ failure → crossover loss → meiotic arrest → ovarian insufficiency. No contradictory findings were identified.

Limitations and Knowledge Gaps

  1. Small patient numbers. Core phenotype frequencies (e.g., 100% secondary amenorrhea/elevated FSH) derive from the 2-sibling index family; broader cohorts are needed to establish robust penetrance and expressivity estimates.
  2. No direct human ovarian histology/omics. The oocyte-apoptosis and follicle-depletion steps are inferred from mouse and comparative data, not demonstrated in human MSH4-deficient ovary. No POF20-specific transcriptomic, proteomic, metabolomic, or single-cell datasets exist.
  3. Penetrance/expressivity. The genotype–phenotype relationship (why some carriers show primary amenorrhea vs milder DOR) and the role of modifier/digenic alleles (MSH5) are incompletely resolved.
  4. Epidemiology. No POF20-specific prevalence/incidence figures exist; only the broad POI prevalence (~3.5%) and small panel-based contributions are available.
  5. No disease-modifying therapy or trials. All treatment evidence is generic POI management; no MSH4-targeted therapeutics or NCT-registered trials specific to POF20.
  6. Epigenetic/environmental modifiers of the meiotic phenotype are unstudied in this subtype.

Proposed Follow-up Experiments / Actions

  1. Aggregate an international MSH4-POI cohort (GeneMatcher, large POI consortia) to quantify penetrance, expressivity, genotype–phenotype correlations, and sex-specific outcomes (POI vs NOA).
  2. Functional validation of VUS: minigene splicing assays and MutSγ complex-formation / HJ-binding assays to reclassify uncertain MSH4 missense variants per ACMG/AMP.
  3. Patient-derived iPSC → germ-cell / ovarian organoid models to directly observe meiotic arrest and oocyte apoptosis in the human MSH4-deficient context, filling the inferred mechanistic gap.
  4. Single-cell transcriptomics of residual ovarian tissue / model germ cells to define the apoptotic and granulosa-cell responses downstream of meiotic failure.
  5. Early-diagnosis fertility-preservation protocols: identify biallelic carriers before pool exhaustion to evaluate oocyte/ovarian-tissue cryopreservation windows.
  6. Structured genetic counseling pathway including cascade testing of male siblings (azoospermia risk) and partner carrier screening in consanguineous families.
  7. Longitudinal HRT outcome study in genetically defined POF20 to confirm that estrogen-deprivation sequelae are mitigated as in general POI.

Report compiled from a 5-iteration autonomous investigation: 8 confirmed findings, 34 papers reviewed. The causal gene was corrected from MCM8 to MSH4 during the investigation. Evidence integrates human clinical/genetic reports, mouse knockout models, yeast/invertebrate biochemistry, and the 2024 ESHRE/ASRM/IMS POI guideline.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 35
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 5
Terms whose name was checked 13
Terms named correctly 6
Terms named as a different term 4
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0030975 (6 mentions) - the report calls it "if available"; MONDO calls it premature ovarian failure 20
  • NCIT:C62002 (2 mentions) - the report calls it "Hormone replacement therapy (estradiol + progestogen)"; NCIT calls it Amiodarone
  • NCIT:C713 (2 mentions) - the report calls it "Progestin"; NCIT calls it Oligonucleotide
  • NCIT:C92755 (2 mentions) - the report calls it "Oocyte donation"; NCIT calls it Chorionic Villus Sampling

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0008232 (3 mentions) - the report calls it "Elevated circulating FSH"; HP calls it Elevated circulating follicle stimulating hormone level, and lists "Elevated follicle stimulating hormone" among its other names
  • HP:0011969 (3 mentions) - the report calls it "Elevated circulating LH"; HP calls it Elevated circulating luteinizing hormone level
  • NCIT:C617 (2 mentions) - the report calls it "Estrogen"; NCIT calls it Lomustine, and lists "Belustin" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, UMLS, GARD.