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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected women carry homozygous variants (several from consanguineous families) or compound-heterozygous variants, with heterozygous parents. No penetrance value is assigned. Male carriers are not reported to be affected, consistent with the fertility of male Mos-null mice.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:34779126 SUPPORT Human clinical

"Here, we identified four rare variants of MOS in three infertile female individuals with EEAF that followed a recessive inheritance pattern."

Recessive segregation in the three founding families.

PMID:34997960 SUPPORT Human clinical

"We identified recessive mutations in MOS in two independent patients with the PREMBA phenotype."

Independent cohort with recessive genotypes.

PMID:35670744 SUPPORT Human clinical

"The MOS variants followed a recessive inheritance pattern in infertile patients."

Recessive inheritance in the large-polar-body families.

⚙

Pathophysiology

6

Biallelic MOS Loss-of-Function Variants

Reported genotypes combine missense variants across the kinase domain with nonsense and frameshift alleles. In transfected HEK293 cells and in mouse oocytes, the variant proteins are expressed at lower levels, bind MEK1 more weakly, or both, and fail to phosphorylate MEK1/2. MOS is a MAP kinase kinase kinase whose expression is essentially restricted to the oocyte, which is why the phenotype is confined to female reproduction.

oocyte CL:0000023

MOS hgnc:7199

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Biallelic missense, nonsense (p.Cys320Ter) and frameshift (p.Gly156Alafs*18) variants; missense alleles retain varying residual activity in the functional assays.

MOS kinase activity toward MEK1/2 GO:0004709 ↓ DECREASED

Downstream

Oocyte MEK-ERK1/2 Cascade Inactivation MOS is the kinase that phosphorylates MEK1/2 in the maturing oocyte; without it MEK1/2 and then ERK1/2 are not activated.

Show evidence (3 references)

PMID:34779126 SUPPORT In vitro / ex vivo

"Therefore, we concluded that MOS variants mainly lead to MEK/ERK inactivation through the decreased MOS protein or weaker MEK1 interaction."

Patient variants reduce MOS protein or its MEK1 binding.

PMID:34997960 SUPPORT In vitro / ex vivo

"The mutations c.285C>A (p.(Asn95Lys)) and c.467delG (p.(Gly156Alafs*18)) reduced the protein level of MOS, and all mutations reduced the ability of MOS to phosphorylate its downstream target, extracellular signal-regulated kinase1/2."

Independent functional confirmation in HEK293T cells.

PMID:35670744 SUPPORT In vitro / ex vivo

"In addition, when compared with wild-type MOS, the MOS variants decreased the MOS protein level and attenuated the binding capacity with MEK1."

A third variant set shows the same loss of protein and MEK1 binding.

Oocyte MEK-ERK1/2 Cascade Inactivation

In control human oocytes phosphorylated ERK1/2 is weak at the germinal vesicle stage, strong at metaphase II, and lost after fertilization. Unfertilized metaphase II oocytes from a homozygous patient show reduced phosphorylated ERK1/2, and patient variants fail to restore ERK1/2 activation in mouse oocytes depleted of endogenous Mos.

oocyte CL:0000023

ERK1 hgnc:6877 ERK2 hgnc:6871

ERK1 and ERK2 cascade GO:0070371 ↓ DECREASED

Downstream

Failed Metaphase II Arrest MOS-ERK signalling is the cytostatic factor that maintains metaphase II arrest of the unfertilized egg.

Cortical Actin and Spindle Assembly Defects in Oocytes ERK1/2 activity is required for cortical F-actin thickening and spindle assembly in the maturing oocyte.

Impaired Maternal mRNA Clearance During Oocyte Maturation Maturation-directed decay of maternal transcripts depends on MOS-ERK signalling.

Show evidence (3 references)

PMID:34779126 SUPPORT Human clinical

"Moreover, the pERK1/2 levels were significantly decreased in the unfertilized oocytes of patient 1 compared with those in the control oocytes from unidentified patients"

Reduced ERK1/2 activation measured directly in patient oocytes.

PMID:35670744 SUPPORT In vitro / ex vivo

"The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes and HEK293 cells."

Variants from the large-polar-body families also fail to activate the cascade.

PMID:34806827 SUPPORT REVIEW SYNTHESIS Human clinical

"Bi-allelic pathogenic variants in MOS inactivate the MOS-ERK pathway and therefore cause disruption of cytoskeleton assembly, mRNA clearance, and mitochondrial homeostasis"

Commentary summarizing the founding study's model, in which ERK inactivation is the hub for the three downstream branches.

Failed Metaphase II Arrest

Without the MOS-ERK cytostatic signal, mature eggs do not hold at metaphase II and can complete meiosis and begin cleavage without fertilization. This is the defining phenotype of Mos-null mouse eggs. In women it has been documented directly in one patient, whose oocytes activated parthenogenetically in two IVF cycles; in the other reported families its contribution to the embryo phenotype is inferred.

oocyte CL:0000023

premature metaphase/anaphase transition of meiosis II GO:1990950 ↕ DYSREGULATED

Animal models

Mos-null mouse Mouse recapitulates Source of the metaphase II arrest node.

Downstream

Parthenogenetic Oocyte Activation An egg that exits metaphase II without fertilization activates parthenogenetically.

Show evidence (3 references)

PMID:8015609 SUPPORT Model organism

"In contrast, mutant females, have a reduced fertility because of the failure of mature eggs to arrest during meiosis."

Mos-null eggs fail to arrest in meiosis.

PMID:8015610 SUPPORT Model organism

"The results indicate that in mice Mos plays a role in the second meiotic metaphase arrest, but does not seem to be essential for the initiation of oocyte maturation, spermatogenesis or somatic cell cycle."

Independent knockout localizing the requirement to metaphase II arrest.

PMID:42109071 SUPPORT Human clinical

"variant c 573 C > A results in the formation of a large PB and parthenogenetic activation as reported in animal models earlier."

Parthenogenetic activation observed in a patient's oocytes.

Cortical Actin and Spindle Assembly Defects in Oocytes

MOS-ERK signalling thickens the cortical F-actin layer and supports spindle assembly during oocyte maturation, which together position the spindle so the first meiotic division is asymmetric. Mos knockdown, oocyte-specific Erk1/2 deletion, or MEK inhibition of human oocytes reduces cortical F-actin and destabilizes alpha-tubulin, and patient MOS variants fail to restore cortical F-actin after Mos knockdown. The authors propose these cytoskeletal defects as the origin of the large first polar body and of embryo fragmentation; the second link is a hypothesis rather than a demonstrated mechanism.

oocyte CL:0000023

cortical actin cytoskeleton organization GO:0030866 ↓ DECREASED

Animal models

Oocyte-specific Erk1/2 knockout mouse Mouse recapitulates Genetic evidence that ERK1/2 is required for oocyte cortical F-actin.

Downstream

Large First Polar Body Without a thickened cortex and positioned spindle the first meiotic division becomes symmetric, producing an oversized polar body; wild-type but not variant MOS reverses this in Mos-depleted mouse oocytes.

Embryo Fragmentation Proposed by the authors to explain fragmentation in arrested embryos; the steps from oocyte cytoskeletal defects to blastomere fragmentation are not defined.

Show evidence (3 references)

PMID:34779126 SUPPORT In vitro / ex vivo

"These MOS variants encoded proteins that resulted in decreased phosphorylated ERK1/2 level in cells and oocytes, and displayed attenuated rescuing effects on cortical F-actin assembly."

Patient variants cannot restore cortical F-actin in Mos-depleted mouse oocytes.

PMID:34779126 SUPPORT Model organism

"ERK1/2 deficiency in oocytes caused very low cortical F-actin and TPX2 signals, in which the latter one is a marker of spindle assembly"

Oocyte-specific Erk1/2 deletion reduces cortical F-actin and spindle assembly.

PMID:34997960 SUPPORT In vitro / ex vivo

"the F-actin cytoskeleton of mouse oocytes was affected by the patient-derived mutations."

Independent cohort reports the same F-actin effect.

Impaired Maternal mRNA Clearance During Oocyte Maturation

During normal human oocyte maturation thousands of maternal transcripts are degraded. In metaphase II oocytes from a patient homozygous for p.Asn95Lys, and in control human oocytes matured with the MEK inhibitor U0126, a large set of these transcripts persists; the retained set is enriched for mitochondrial respiratory-chain and mitochondrial translation genes.

oocyte CL:0000023

maternal mRNA clearance GO:0141065 ↓ DECREASED

Downstream

Oocyte Mitochondrial Dysfunction The authors attribute the mitochondrial defect to failed clearance of mitochondrial transcripts; this link is correlative.

Show evidence (1 reference)

PMID:34779126 SUPPORT Human clinical

"RNA-sequencing results revealed that substantial maternal mRNAs' clearance during oocyte maturation was retarded either in mature oocytes carrying MOSAsn95Lys variant or in U0126-treated oocytes, in which the most affected transcripts were enriched in mitochondrial biological process."

Transcriptome of patient oocytes shows retarded maternal mRNA clearance, matched by pharmacological ERK inhibition of control oocytes.

Oocyte Mitochondrial Dysfunction

Inhibiting ERK1/2 activation lowers ATP content and mitochondrial membrane potential in human and mouse metaphase II oocytes, and oocyte-specific Erk1/2 knockout oocytes show the same defect with mitochondria mislocalized into the polar body. This has not been measured in patient oocytes. No GO term is bound: the measured readouts are ATP level and membrane potential, and GO:0007005 mitochondrion organization would assert a structural process that was not tested.

oocyte CL:0000023

Downstream

Embryo Developmental Arrest Reduced oocyte energy capacity is proposed to compromise early cleavage; which defect is limiting for development is not known.

Show evidence (1 reference)

PMID:34779126 SUPPORT In vitro / ex vivo

"Furthermore, inactivation of MOS-ERK signal cascade caused mitochondrial dysfunction of mature oocytes."

Pharmacological and genetic ERK inactivation impairs oocyte mitochondria.

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Pathograph

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Phenotypes

5

Genitourinary 2

Female Infertility HP:0008222

Show evidence (2 references)

PMID:34779126 SUPPORT Human clinical

"They had normal menstrual cycles and sex hormone levels"

Infertile probands with otherwise normal reproductive endocrinology.

PMID:42109071 SUPPORT Human clinical

"A thirty-year-old woman with 12 years of infertility underwent two in vitro fertilization cycles"

Long-standing infertility in an independent case.

Parthenogenetic Oocyte Activation Abnormal female meiosis HP:0033338

Sequelae: Female Infertility

Show evidence (2 references)

PMID:42109071 SUPPORT Human clinical

"in both she had oocytes with large PBs and parthenogenetic activation"

Parthenogenetic activation in a homozygous p.Phe191Leu patient.

PMID:8015609 SUPPORT Model organism

"These results demonstrate that a major role for pp39mos is to prevent the spontaneous parthenogenetic activation of unfertilized eggs."

Parthenogenetic activation is the core Mos-null mouse phenotype.

Prenatal and Birth 2

Embryo Developmental Arrest HP:0020003

Sequelae: Female Infertility

Show evidence (3 references)

PMID:34779126 SUPPORT Human clinical

"all zygotes consistently arrested at the two- to five-cell stage"

Cleavage-stage arrest of every zygote in one proband's ICSI cycle.

PMID:34779126 SUPPORT Human clinical

"nine zygotes were cleaved at the two- to seven-cell stage on day 3 and arrested during subsequent blastocyst culture"

Every cleaved embryo of a second proband arrested before blastocyst.

PMID:34779126 SUPPORT Human clinical

"Proband II-1 in family 2 had undergone four separate ICSI attempts, and three previous failed attempts in other hospitals were diagnosed as embryonic arrest"

Arrest recurs across repeated ICSI cycles, so bypassing sperm entry by ICSI does not rescue embryo development.

Embryo Fragmentation Abnormal preimplantation embryonic development HP:0033335

Sequelae: Female Infertility

Show evidence (2 references)

PMID:34779126 SUPPORT Human clinical

"six of seven arrested embryos with severe fragmentation were produced during the first cleavage"

Severe fragmentation in a proband's arrested embryos.

PMID:34779126 SUPPORT Model organism

"only 4.7% of the embryos developed into blastocysts (Fig 3F), 25% embryos were severely fragmented"

Embryos from Erk1/2-deleted mouse oocytes reproduce arrest with fragmentation.

Cellular 1

Large First Polar Body Abnormal oocyte morphology HP:0020155

Sequelae: Female Infertility

Show evidence (3 references)

PMID:35670744 SUPPORT Human clinical

"All three patients displayed a high percentage of large PB1 extrusion in the oocytes."

Large first polar body in two independent families.

PMID:36403623 SUPPORT Human clinical

"These findings suggest that MOS mutation results in oocytes with a large polar body and poor embryonic development in patients."

A further homozygous proband with large polar body oocytes.

PMID:35670744 SUPPORT In vitro / ex vivo

"Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed the symmetric division of oocytes after siMos treatment. In contrast, the three MOS variants demonstrated no rescuing ability."

Symmetric division in Mos-depleted mouse oocytes is rescued only by wild-type MOS.

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Genetic Associations

1

MOS (Causative)

Gene: MOS (MOS proto-oncogene, serine/threonine kinase) hgnc:7199 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:34779126 SUPPORT Human clinical

"This study firstly provides direct evidence that biallelic MOS mutation is associated with EEAF phenotype and female infertility"

Founding report establishing MOS as a causal gene.

PMID:34997960 SUPPORT Human clinical

"the effects of the mutations in human embryonic kidney 293T (HEK293T cells) and mouse oocytes provided evidence for a causal relation between MOS and female infertility."

Independent replication with functional support.

Variants (4)

c.285C>A (p.Asn95Lys)

missense variant

Homozygous missense in a proband from a consanguineous family, and in a second independent cohort; reduces MOS protein and MEK1 binding.

Show evidence (1 reference)

PMID:34997960 SUPPORT Human clinical

"We identified the homozygous missense mutation c.285C>A (p.(Asn95Lys)) and the compound heterozygous mutations c.467delG (p.(Gly156Alafs*18)) and c.956G>A (p.(Arg319His)) in MOS in two independent patients."

Recurrence of p.Asn95Lys in a second cohort, with the other variants found there.

c.960C>A (p.Cys320Ter)

stop gained

Homozygous nonsense variant; the truncated protein hardly binds MEK1.

Show evidence (1 reference)

PMID:34779126 SUPPORT Human clinical

"They carry homozygous missense variant c.285C>A (p. Asn95Lys), homozygous nonsense variant c.960C>A (p. Cys320Ter), and compound heterozygous missense variants c.416T>C (p. Met139Thr) and c.737G>A (p. Arg246His), respectively."

Genotypes of the three founding probands.

c.791C>G (homozygous); c.596A>T and c.875C>T (compound heterozygous)

missense variant

Missense variants in the large-polar-body families; none activates MEK1/2 or ERK1/2 in oocytes.

Show evidence (1 reference)

PMID:35670744 SUPPORT Human clinical

"We identified three rare missense variants in MOS, including a homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and two compound missense variants (c.596A>T and c.875C>T) from twin sisters in Family 2."

Large-polar-body genotypes.

c.573C>A (p.Phe191Leu)

missense variant

Homozygous missense in a patient with large polar bodies and parthenogenetic activation.

Show evidence (1 reference)

PMID:42109071 SUPPORT Human clinical

"Clinical exome sequence was performed and revealed a novel homozygous variant in MOS (NM_005372.1):c.573C > A;p.(Phe191Leu)."

Genotype of the parthenogenetic-activation case.

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Diagnosis

1

Genetic testing after repeated IVF/ICSI failure

Exome sequencing or a female-infertility gene panel including MOS can be considered for women with repeated IVF/ICSI failure from cleavage-stage arrest with fragmentation, large first polar bodies, or parthenogenetic oocyte activation. Biallelic variants should be confirmed in trans by parental testing.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:34997960 SUPPORT Human clinical

"suggest that mutations in MOS may be precise diagnostic markers for clinical genetic counselling."

Authors propose MOS as a diagnostic marker.

PMID:35670744 SUPPORT Human clinical

"Our study findings facilitate the early genetic diagnosis of abnormal oocyte morphology characterized as large PB1 that eventually causes infertility in women."

Extends the diagnostic indication to the large-polar-body presentation.

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Animal Models

2

Mos-null mouse

Two independent Mos knockouts. Mice are viable and males are fertile. Females have low fertility because mature eggs fail to hold at metaphase II and activate parthenogenetically; they also develop ovarian cysts or teratomas, which are not reported in patients.

Species

Mouse

Genotype

Mos-/- (germline gene-targeted)

Publication

PMID:8015609

Pathograph links

Failed Metaphase II Arrest recapitulates fidelity: high Source of the metaphase II arrest node.

Limitations: A complete germline null, whereas most patient alleles are missense variants with residual activity; mouse eggs mostly undergo parthenogenetic activation, while most patients present with post-fertilization cleavage arrest instead.

Show evidence (2 references)

PMID:8015609 SUPPORT Model organism

"c-mos-/- oocytes undergo germinal vesicle breakdown and extrusion of both polar bodies followed in some cases by progression into cleavage."

Mos-null eggs complete meiosis and cleave without fertilization.

+ 1 more reference

Oocyte-specific Erk1/2 knockout mouse

Deleting ERK1/2 in oocytes reproduces the human phenotype downstream of MOS: mature eggs with large and multiple polar bodies, low cortical F-actin, mitochondrial dysfunction, and embryos that arrest or fragment.

Species

Mouse

Genotype

Erk1-/-; Erk2 flox/flox; Gdf9-Cre

Publication

PMID:34779126

Pathograph links

Cortical Actin and Spindle Assembly Defects in Oocytes recapitulates fidelity: moderate Genetic evidence that ERK1/2 is required for oocyte cortical F-actin.

Limitations: Removes the effector kinases rather than MOS itself, so it cannot distinguish MOS-specific from other ERK-activating inputs.

Show evidence (1 reference)

PMID:34779126 SUPPORT Model organism

"ERK1/2 deficiency in oocytes caused very low cortical F-actin and TPX2 signals, in which the latter one is a marker of spindle assembly"

Cortical actin and spindle defect in knockout oocytes.

{ }

Source YAML

click to show

name: MOS-related Oocyte Zygote Embryo Maturation Arrest
creation_date: "2026-10-30T03:40:00Z"
category: Mendelian
disease_term:
preferred_term: oocyte/zygote/embryo maturation arrest 20
term:
id: MONDO:0957278
label: oocyte/zygote/embryo maturation arrest 20
synonyms:
- oocyte/zygote/embryo maturation arrest 20
- OZEMA20
- MOS-related female infertility
- MOS-related early embryonic arrest and fragmentation
description: >-
MOS-related oocyte/zygote/embryo maturation arrest is an autosomal-recessive
form of primary female infertility caused by biallelic loss-of-function
variants in MOS, the oocyte-specific serine/threonine kinase that
phosphorylates MEK1/2 and so activates ERK1/2 during meiotic maturation.
In vertebrate oocytes MOS-ERK signalling is the cytostatic factor that holds
the mature egg at metaphase II until fertilization, and it also organizes
the cortical actin and spindle that make the first meiotic division
asymmetric. Affected women have normal menstrual cycles and hormone levels;
they are identified after repeated IVF/ICSI failure. Most retrieved oocytes
reach metaphase II, but embryos arrest at the cleavage stage, often with
severe fragmentation, and in other families oocytes extrude an abnormally
large first polar body or activate without fertilization. Patient variants
lower MOS protein or weaken its binding to MEK1 and fail to activate ERK1/2
in cultured cells and mouse oocytes; patient oocytes show reduced
phosphorylated ERK1/2, retarded maternal mRNA clearance, and loss of
cortical F-actin. Female Mos-null mice show the parallel phenotype of
spontaneous parthenogenetic egg activation and low fertility. Ten affected
women have been reported, mostly from Chinese infertility cohorts, and no
treatment is established.
parents:
- hereditary disease
- female reproductive system disease
references:
- reference: PMID:34779126
title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
- reference: PMID:34806827
title: MOS is a novel genetic marker for human early embryonic arrest and fragmentation.
- reference: PMID:34997960
title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
- reference: PMID:35670744
title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
- reference: PMID:36403623
title: MOS mutation causes female infertility with large polar body oocytes.
- reference: PMID:42109071
title: A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.
- reference: PMID:8015609
title: Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs.
- reference: PMID:8015610
title: Parthenogenetic activation of oocytes in c-mos-deficient mice.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Affected women carry homozygous variants (several from consanguineous
families) or compound-heterozygous variants, with heterozygous parents. No
penetrance value is assigned. Male carriers are not reported to be
affected, consistent with the fertility of male Mos-null mice.
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we identified four rare variants of MOS in three infertile female
individuals with EEAF that followed a recessive inheritance pattern.
explanation: Recessive segregation in the three founding families.
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified recessive mutations in MOS in two independent patients
with the PREMBA phenotype.
explanation: Independent cohort with recessive genotypes.
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The MOS variants followed a recessive inheritance pattern in infertile
patients.
explanation: Recessive inheritance in the large-polar-body families.
pathophysiology:
- name: Biallelic MOS Loss-of-Function Variants
role: TRIGGER
biological_scale: MOLECULAR
description: >-
Reported genotypes combine missense variants across the kinase domain with
nonsense and frameshift alleles. In transfected HEK293 cells and in mouse
oocytes, the variant proteins are expressed at lower levels, bind MEK1
more weakly, or both, and fail to phosphorylate MEK1/2. MOS is a MAP
kinase kinase kinase whose expression is essentially restricted to the
oocyte, which is why the phenotype is confined to female reproduction.
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
description: >-
Biallelic missense, nonsense (p.Cys320Ter) and frameshift
(p.Gly156Alafs*18) variants; missense alleles retain varying residual
activity in the functional assays.
genes:
- preferred_term: MOS
term:
id: hgnc:7199
label: MOS
molecular_functions:
- preferred_term: MOS kinase activity toward MEK1/2
term:
id: GO:0004709
label: MAP kinase kinase kinase activity
modifier: DECREASED
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Therefore, we concluded that MOS variants mainly lead to MEK/ERK
inactivation through the decreased MOS protein or weaker MEK1
interaction.
explanation: Patient variants reduce MOS protein or its MEK1 binding.
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The mutations c.285C>A (p.(Asn95Lys)) and c.467delG (p.(Gly156Alafs*18))
reduced the protein level of MOS, and all mutations reduced the ability
of MOS to phosphorylate its downstream target, extracellular
signal-regulated kinase1/2.
explanation: Independent functional confirmation in HEK293T cells.
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In addition, when compared with wild-type MOS, the MOS variants decreased
the MOS protein level and attenuated the binding capacity with MEK1.
explanation: A third variant set shows the same loss of protein and MEK1 binding.
downstream:
- target: Oocyte MEK-ERK1/2 Cascade Inactivation
description: >-
MOS is the kinase that phosphorylates MEK1/2 in the maturing oocyte;
without it MEK1/2 and then ERK1/2 are not activated.
- name: Oocyte MEK-ERK1/2 Cascade Inactivation
biological_scale: MOLECULAR
description: >-
In control human oocytes phosphorylated ERK1/2 is weak at the germinal
vesicle stage, strong at metaphase II, and lost after fertilization.
Unfertilized metaphase II oocytes from a homozygous patient show reduced
phosphorylated ERK1/2, and patient variants fail to restore ERK1/2
activation in mouse oocytes depleted of endogenous Mos.
genes:
- preferred_term: ERK1
term:
id: hgnc:6877
label: MAPK3
- preferred_term: ERK2
term:
id: hgnc:6871
label: MAPK1
biological_processes:
- preferred_term: ERK1 and ERK2 cascade
term:
id: GO:0070371
label: ERK1 and ERK2 cascade
modifier: DECREASED
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moreover, the pERK1/2 levels were significantly decreased in the
unfertilized oocytes of patient 1 compared with those in the control
oocytes from unidentified patients
explanation: Reduced ERK1/2 activation measured directly in patient oocytes.
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The three MOS variants could not activate MEK1/2 and ERK1/2 in oocytes
and HEK293 cells.
explanation: Variants from the large-polar-body families also fail to activate the cascade.
- reference: PMID:34806827
reference_title: MOS is a novel genetic marker for human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
snippet: >-
Bi-allelic pathogenic variants in MOS inactivate the MOS-ERK pathway and
therefore cause disruption of cytoskeleton assembly, mRNA clearance, and
mitochondrial homeostasis
explanation: >-
Commentary summarizing the founding study's model, in which ERK
inactivation is the hub for the three downstream branches.
downstream:
- target: Failed Metaphase II Arrest
description: >-
MOS-ERK signalling is the cytostatic factor that maintains metaphase II
arrest of the unfertilized egg.
- target: Cortical Actin and Spindle Assembly Defects in Oocytes
description: >-
ERK1/2 activity is required for cortical F-actin thickening and spindle
assembly in the maturing oocyte.
- target: Impaired Maternal mRNA Clearance During Oocyte Maturation
description: >-
Maturation-directed decay of maternal transcripts depends on MOS-ERK
signalling.
- name: Failed Metaphase II Arrest
biological_scale: CELLULAR
description: >-
Without the MOS-ERK cytostatic signal, mature eggs do not hold at
metaphase II and can complete meiosis and begin cleavage without
fertilization. This is the defining phenotype of Mos-null mouse eggs. In
women it has been documented directly in one patient, whose oocytes
activated parthenogenetically in two IVF cycles; in the other reported
families its contribution to the embryo phenotype is inferred.
biological_processes:
- preferred_term: premature metaphase/anaphase transition of meiosis II
term:
id: GO:1990950
label: metaphase/anaphase transition of meiosis II
modifier: DYSREGULATED
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:8015609
reference_title: Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In contrast, mutant females, have a reduced fertility because of the
failure of mature eggs to arrest during meiosis.
explanation: Mos-null eggs fail to arrest in meiosis.
- reference: PMID:8015610
reference_title: Parthenogenetic activation of oocytes in c-mos-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The results indicate that in mice Mos plays a role in the second meiotic
metaphase arrest, but does not seem to be essential for the initiation
of oocyte maturation, spermatogenesis or somatic cell cycle.
explanation: Independent knockout localizing the requirement to metaphase II arrest.
- reference: PMID:42109071
reference_title: A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
variant c 573 C > A results in the formation of a large PB and
parthenogenetic activation as reported in animal models earlier.
explanation: Parthenogenetic activation observed in a patient's oocytes.
downstream:
- target: Parthenogenetic Oocyte Activation
description: >-
An egg that exits metaphase II without fertilization activates
parthenogenetically.
- name: Cortical Actin and Spindle Assembly Defects in Oocytes
biological_scale: CELLULAR
description: >-
MOS-ERK signalling thickens the cortical F-actin layer and supports
spindle assembly during oocyte maturation, which together position the
spindle so the first meiotic division is asymmetric. Mos knockdown,
oocyte-specific Erk1/2 deletion, or MEK inhibition of human oocytes
reduces cortical F-actin and destabilizes alpha-tubulin, and patient MOS
variants fail to restore cortical F-actin after Mos knockdown. The
authors propose these cytoskeletal defects as the origin of the large
first polar body and of embryo fragmentation; the second link is a
hypothesis rather than a demonstrated mechanism.
biological_processes:
- preferred_term: cortical actin cytoskeleton organization
term:
id: GO:0030866
label: cortical actin cytoskeleton organization
modifier: DECREASED
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These MOS variants encoded proteins that resulted in decreased
phosphorylated ERK1/2 level in cells and oocytes, and displayed
attenuated rescuing effects on cortical F-actin assembly.
explanation: Patient variants cannot restore cortical F-actin in Mos-depleted mouse oocytes.
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
ERK1/2 deficiency in oocytes caused very low cortical F-actin and TPX2
signals, in which the latter one is a marker of spindle assembly
explanation: Oocyte-specific Erk1/2 deletion reduces cortical F-actin and spindle assembly.
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the F-actin cytoskeleton of mouse oocytes was affected by the
patient-derived mutations.
explanation: Independent cohort reports the same F-actin effect.
downstream:
- target: Large First Polar Body
description: >-
Without a thickened cortex and positioned spindle the first meiotic
division becomes symmetric, producing an oversized polar body; wild-type
but not variant MOS reverses this in Mos-depleted mouse oocytes.
- target: Embryo Fragmentation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed by the authors to explain fragmentation in arrested embryos;
the steps from oocyte cytoskeletal defects to blastomere fragmentation
are not defined.
- name: Impaired Maternal mRNA Clearance During Oocyte Maturation
biological_scale: MOLECULAR
description: >-
During normal human oocyte maturation thousands of maternal transcripts
are degraded. In metaphase II oocytes from a patient homozygous for
p.Asn95Lys, and in control human oocytes matured with the MEK inhibitor
U0126, a large set of these transcripts persists; the retained set is
enriched for mitochondrial respiratory-chain and mitochondrial translation
genes.
biological_processes:
- preferred_term: maternal mRNA clearance
term:
id: GO:0141065
label: maternal mRNA clearance
modifier: DECREASED
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
RNA-sequencing results revealed that substantial maternal mRNAs'
clearance during oocyte maturation was retarded either in mature oocytes
carrying MOSAsn95Lys variant or in U0126-treated oocytes, in which the
most affected transcripts were enriched in mitochondrial biological
process.
explanation: >-
Transcriptome of patient oocytes shows retarded maternal mRNA
clearance, matched by pharmacological ERK inhibition of control oocytes.
downstream:
- target: Oocyte Mitochondrial Dysfunction
description: >-
The authors attribute the mitochondrial defect to failed clearance of
mitochondrial transcripts; this link is correlative.
- name: Oocyte Mitochondrial Dysfunction
biological_scale: CELLULAR
description: >-
Inhibiting ERK1/2 activation lowers ATP content and mitochondrial
membrane potential in human and mouse metaphase II oocytes, and
oocyte-specific Erk1/2 knockout oocytes show the same defect with
mitochondria mislocalized into the polar body. This has not been
measured in patient oocytes. No GO term is bound: the measured readouts
are ATP level and membrane potential, and GO:0007005 mitochondrion
organization would assert a structural process that was not tested.
cell_types:
- preferred_term: oocyte
term:
id: CL:0000023
label: oocyte
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Furthermore, inactivation of MOS-ERK signal cascade caused mitochondrial
dysfunction of mature oocytes.
explanation: Pharmacological and genetic ERK inactivation impairs oocyte mitochondria.
downstream:
- target: Embryo Developmental Arrest
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Reduced oocyte energy capacity is proposed to compromise early
cleavage; which defect is limiting for development is not known.
phenotypes:
- name: Female Infertility
description: >-
Primary infertility presenting as repeated IVF/ICSI failure in women with
normal menstrual cycles and sex hormone levels.
phenotype_term:
preferred_term: Female infertility
term:
id: HP:0008222
label: Female infertility
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They had normal menstrual cycles and sex hormone levels
explanation: Infertile probands with otherwise normal reproductive endocrinology.
- reference: PMID:42109071
reference_title: A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A thirty-year-old woman with 12 years of infertility underwent two in
vitro fertilization cycles
explanation: Long-standing infertility in an independent case.
- name: Embryo Developmental Arrest
description: >-
Fertilized embryos arrest at the cleavage stage, typically between the
one-cell and seven-cell stage, and none reaches the blastocyst stage in
the founding families. Arrest recurs across repeated IVF and ICSI
cycles.
phenotype_term:
preferred_term: Embryo developmental arrest
term:
id: HP:0020003
label: Embryo developmental arrest
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all zygotes consistently arrested at the two- to five-cell stage
explanation: Cleavage-stage arrest of every zygote in one proband's ICSI cycle.
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
nine zygotes were cleaved at the two- to seven-cell stage on day 3 and
arrested during subsequent blastocyst culture
explanation: Every cleaved embryo of a second proband arrested before blastocyst.
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Proband II-1 in family 2 had undergone four separate ICSI attempts, and
three previous failed attempts in other hospitals were diagnosed as
embryonic arrest
explanation: >-
Arrest recurs across repeated ICSI cycles, so bypassing sperm entry by
ICSI does not rescue embryo development.
sequelae:
- target: Female Infertility
description: Arrested embryos cannot be transferred.
- name: Embryo Fragmentation
description: >-
Severe fragmentation of cleavage-stage embryos into anucleate fragments,
seen in most arrested embryos in two of the three founding probands.
Bound to the parent term because HPO has no embryo-fragmentation term
(OLS search of HP for "embryo fragmentation" and "fragmentation" returned
only skeletal epiphyseal fragmentation terms).
phenotype_term:
preferred_term: Embryo fragmentation
term:
id: HP:0033335
label: Abnormal preimplantation embryonic development
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
six of seven arrested embryos with severe fragmentation were produced
during the first cleavage
explanation: Severe fragmentation in a proband's arrested embryos.
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
only 4.7% of the embryos developed into blastocysts (Fig 3F), 25% embryos
were severely fragmented
explanation: Embryos from Erk1/2-deleted mouse oocytes reproduce arrest with fragmentation.
sequelae:
- target: Female Infertility
description: Severely fragmented embryos do not develop to transfer.
- name: Large First Polar Body
description: >-
A high proportion of oocytes extrude an abnormally large first polar body,
the result of a near-symmetric first meiotic division. This is the
presenting phenotype in three further families. Bound to the parent term
because HPO has no polar-body term (OLS search of HP for "polar body"
returned no polar-body class).
phenotype_term:
preferred_term: Large first polar body
term:
id: HP:0020155
label: Abnormal oocyte morphology
evidence:
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All three patients displayed a high percentage of large PB1 extrusion in
the oocytes.
explanation: Large first polar body in two independent families.
- reference: PMID:36403623
reference_title: MOS mutation causes female infertility with large polar body oocytes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings suggest that MOS mutation results in oocytes with a large
polar body and poor embryonic development in patients.
explanation: A further homozygous proband with large polar body oocytes.
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Microinjection of wild-type human MOS complementary RNAs (cRNAs) reversed
the symmetric division of oocytes after siMos treatment. In contrast, the
three MOS variants demonstrated no rescuing ability.
explanation: Symmetric division in Mos-depleted mouse oocytes is rescued only by wild-type MOS.
sequelae:
- target: Female Infertility
description: Oocytes with a large polar body develop poorly after fertilization.
- name: Parthenogenetic Oocyte Activation
description: >-
Unfertilized oocytes activate and begin development without
fertilization. Reported in one patient across two IVF cycles; it is the
characteristic phenotype of Mos-null mouse eggs. Bound to the parent term
because HPO has no parthenogenetic-activation term (OLS search of HP for
"parthenogenetic" returned nothing relevant).
phenotype_term:
preferred_term: Parthenogenetic oocyte activation
term:
id: HP:0033338
label: Abnormal female meiosis
evidence:
- reference: PMID:42109071
reference_title: A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in both she had oocytes with large PBs and parthenogenetic activation
explanation: Parthenogenetic activation in a homozygous p.Phe191Leu patient.
- reference: PMID:8015609
reference_title: Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These results demonstrate that a major role for pp39mos is to prevent
the spontaneous parthenogenetic activation of unfertilized eggs.
explanation: Parthenogenetic activation is the core Mos-null mouse phenotype.
sequelae:
- target: Female Infertility
description: Eggs that activate before fertilization cannot develop normally.
genetic:
- name: MOS
association: Causative
relationship_type: CAUSATIVE
gene_term:
preferred_term: MOS (MOS proto-oncogene, serine/threonine kinase)
term:
id: hgnc:7199
label: MOS
notes: >-
Ten affected women from eight families have been reported in five
studies, most from Chinese infertility cohorts. Missense variants cluster in the kinase domain
(residues 60-341). Presentation varies between cleavage-stage arrest with
fragmentation and large first polar body with or without parthenogenetic
activation; whether this tracks residual kinase activity of the allele is
not established. The ClinGen gene-disease validity export committed in
cache/clingen/gene_validity.csv (file created 2026-01-24) has no MOS
record, so no validity tier is recorded.
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study firstly provides direct evidence that biallelic MOS mutation
is associated with EEAF phenotype and female infertility
explanation: Founding report establishing MOS as a causal gene.
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the effects of the mutations in human embryonic kidney 293T (HEK293T
cells) and mouse oocytes provided evidence for a causal relation between
MOS and female infertility.
explanation: Independent replication with functional support.
variants:
- name: c.285C>A (p.Asn95Lys)
description: >-
Homozygous missense in a proband from a consanguineous family, and in a
second independent cohort; reduces MOS protein and MEK1 binding.
type: missense_variant
evidence:
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified the homozygous missense mutation c.285C>A
(p.(Asn95Lys)) and the compound heterozygous mutations c.467delG
(p.(Gly156Alafs*18)) and c.956G>A (p.(Arg319His)) in MOS in two
independent patients.
explanation: Recurrence of p.Asn95Lys in a second cohort, with the other variants found there.
- name: c.960C>A (p.Cys320Ter)
description: >-
Homozygous nonsense variant; the truncated protein hardly binds MEK1.
type: stop_gained
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They carry homozygous missense variant c.285C>A (p. Asn95Lys),
homozygous nonsense variant c.960C>A (p. Cys320Ter), and compound
heterozygous missense variants c.416T>C (p. Met139Thr) and c.737G>A
(p. Arg246His), respectively.
explanation: Genotypes of the three founding probands.
- name: c.791C>G (homozygous); c.596A>T and c.875C>T (compound heterozygous)
description: >-
Missense variants in the large-polar-body families; none activates MEK1/2
or ERK1/2 in oocytes.
type: missense_variant
evidence:
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified three rare missense variants in MOS, including a
homozygous missense variant (c.791C>G) from Patient 1 in Family 1 and
two compound missense variants (c.596A>T and c.875C>T) from twin
sisters in Family 2.
explanation: Large-polar-body genotypes.
- name: c.573C>A (p.Phe191Leu)
description: >-
Homozygous missense in a patient with large polar bodies and
parthenogenetic activation.
type: missense_variant
evidence:
- reference: PMID:42109071
reference_title: A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical exome sequence was performed and revealed a novel homozygous
variant in MOS (NM_005372.1):c.573C > A;p.(Phe191Leu).
explanation: Genotype of the parthenogenetic-activation case.
diagnosis:
- name: Genetic testing after repeated IVF/ICSI failure
diagnosis_term:
preferred_term: genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
description: >-
Exome sequencing or a female-infertility gene panel including MOS can be
considered for women with repeated IVF/ICSI failure from cleavage-stage
arrest with fragmentation, large first polar bodies, or parthenogenetic
oocyte activation. Biallelic variants should be confirmed in trans by
parental testing.
evidence:
- reference: PMID:34997960
reference_title: Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
suggest that mutations in MOS may be precise diagnostic markers for
clinical genetic counselling.
explanation: Authors propose MOS as a diagnostic marker.
- reference: PMID:35670744
reference_title: Biallelic variants in MOS cause large polar body in oocyte and human female infertility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our study findings facilitate the early genetic diagnosis of abnormal
oocyte morphology characterized as large PB1 that eventually causes
infertility in women.
explanation: Extends the diagnostic indication to the large-polar-body presentation.
animal_models:
- name: Mos-null mouse
species: Mouse
genotype: Mos-/- (germline gene-targeted)
publication: PMID:8015609
description: >-
Two independent Mos knockouts. Mice are viable and males are fertile.
Females have low fertility because mature eggs fail to hold at metaphase
II and activate parthenogenetically; they also develop ovarian cysts or
teratomas, which are not reported in patients.
modeled_mechanisms:
- target: Failed Metaphase II Arrest
relationship: RECAPITULATES
fidelity: HIGH
description: Source of the metaphase II arrest node.
limitations: >-
A complete germline null, whereas most patient alleles are missense
variants with residual activity; mouse eggs mostly undergo
parthenogenetic activation, while most patients present with
post-fertilization cleavage arrest instead.
evidence:
- reference: PMID:8015609
reference_title: Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
c-mos-/- oocytes undergo germinal vesicle breakdown and extrusion of
both polar bodies followed in some cases by progression into cleavage.
explanation: Mos-null eggs complete meiosis and cleave without fertilization.
- reference: PMID:8015610
reference_title: Parthenogenetic activation of oocytes in c-mos-deficient mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Oocytes from these females matured to the second meiotic metaphase
both in vivo and in vitro, but were activated without fertilization.
explanation: Independent knockout with the same phenotype.
- name: Oocyte-specific Erk1/2 knockout mouse
species: Mouse
genotype: Erk1-/-; Erk2 flox/flox; Gdf9-Cre
publication: PMID:34779126
description: >-
Deleting ERK1/2 in oocytes reproduces the human phenotype downstream of
MOS: mature eggs with large and multiple polar bodies, low cortical
F-actin, mitochondrial dysfunction, and embryos that arrest or fragment.
modeled_mechanisms:
- target: Cortical Actin and Spindle Assembly Defects in Oocytes
relationship: RECAPITULATES
fidelity: MODERATE
description: Genetic evidence that ERK1/2 is required for oocyte cortical F-actin.
limitations: >-
Removes the effector kinases rather than MOS itself, so it cannot
distinguish MOS-specific from other ERK-activating inputs.
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
ERK1/2 deficiency in oocytes caused very low cortical F-actin and TPX2
signals, in which the latter one is a marker of spindle assembly
explanation: Cortical actin and spindle defect in knockout oocytes.
- target: Embryo Fragmentation
relationship: RECAPITULATES
fidelity: MODERATE
description: Maternal ERK1/2 loss produces arrest with severe fragmentation.
limitations: >-
Removes the effector kinases rather than MOS itself; mouse embryo
fragmentation may not share the cause of human fragmentation.
evidence:
- reference: PMID:34779126
reference_title: Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Using oocyte-specific Erk1/2 knockout mice, we verified that MOS-ERK
signal pathway inactivation in oocytes caused EEAF as human.
explanation: Oocyte ERK1/2 loss reproduces early embryonic arrest and fragmentation.
notes: >-
No treatment is established. Repeated ICSI cycles failed in the reported
patients (see Embryo Developmental Arrest), and no oocyte or embryo rescue
has been attempted in patients. Mos-null females also develop ovarian teratomas, but no ovarian
neoplasm has been reported in affected women, so it is not listed as a
phenotype.

📚

References & Deep Research

References

8

PMID:34779126

Biallelic mutations in MOS cause female infertility characterized by human early embryonic arrest and fragmentation.

No top-level findings curated for this source.

PMID:34806827

MOS is a novel genetic marker for human early embryonic arrest and fragmentation.

No top-level findings curated for this source.

PMID:34997960

Bi-allelic mutations in MOS cause female infertility characterized by preimplantation embryonic arrest.

No top-level findings curated for this source.

PMID:35670744

Biallelic variants in MOS cause large polar body in oocyte and human female infertility.

No top-level findings curated for this source.

PMID:36403623

MOS mutation causes female infertility with large polar body oocytes.

No top-level findings curated for this source.

PMID:42109071

A novel MOS variant causes large polar body formation and parthenogenetic activation; case report of an unusual phenomenon leading to female infertility.

No top-level findings curated for this source.

PMID:8015609

Disruption of c-mos causes parthenogenetic development of unfertilized mouse eggs.

No top-level findings curated for this source.

PMID:8015610

Parthenogenetic activation of oocytes in c-mos-deficient mice.

No top-level findings curated for this source.

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)

Review round 1: deep-research report and evidence fixes · 2026-10-30T04:42:35Z · View source

Answers the first automated review of PR 15979. Added the Claude Code deep-research report (research/MOS-related_Oocyte_Zygote_Embryo_Maturation_Arrest-deep-research-claude_code.md); just preflight-dr passes against MONDO:0957278 (MOS, OMIM 620383). The report cites no PMIDs and adds no primary source beyond the five patient reports already cited. A PubMed search for MOS with infertility, embryonic arrest or polar body from 2022 to 2026 found no further human MOS cohorts, only mouse mechanism papers, and nothing on oocyte activation, donor oocytes or PGT in MOS patients, so no treatment was added. Evidence changes: the PREMBA snippet that only named the phenotype on Embryo Developmental Arrest was replaced by two quotes from PMID:34779126 describing cleavage arrest and arrest across repeated ICSI cycles, which also now backs the ICSI statement in notes; the commentary PMID:34806827 is cited on the ERK1/2 node as REVIEW_SYNTHESIS; the genetic notes state that the committed ClinGen export has no MOS record; relationship_type CAUSATIVE added on the MOS row.

Claude Code ▸

MOS-related Oocyte/Zygote/Embryo Maturation Arrest (OZEMA20): research report

claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-30T04:41:09.458314

MOS-related Oocyte/Zygote/Embryo Maturation Arrest (OZEMA20): research report

Scope and verification. I ran three web searches and read only the search summaries, not the full texts. Statements from those results are linked. Other statements come from background knowledge and are marked [unverified]. I give no PMIDs because I could not confirm any. The DOI and PMC links below came from the search results. Quotes are paraphrases of search summaries, not verified abstract text, and need exact-snippet checking with just fetch-reference before use as evidence.

The causal gene is MOS (MOS proto-oncogene, serine/threonine kinase, hgnc:7199 [unverified, look up before binding]; UniProt P00540). The disease is OMIM:620383, "Oocyte/zygote/embryo maturation arrest 20" (OZEMA20). The MONDO ID MONDO:0957278 was given in the brief and I did not confirm it.

1. Disease information

OZEMA20 is an autosomal recessive female infertility disorder. Biallelic MOS variants cause early embryonic arrest and fragmentation (EEAF) after fertilization. The oocyte retrieves and fertilizes, but embryos stop in the cleavage stages and fragment (UniProt/OMIM summary via search; Zhang et al. 2021, PMC8649871).
Naming caveat. "Maturation arrest" in the OZEMA series covers oocyte maturation arrest, zygote arrest and embryo arrest as a family. The reported MOS phenotype is mainly early embryonic arrest with fragmentation, not a classic germinal-vesicle or MI oocyte arrest. The searches did not show the full OMIM clinical synopsis, so I could not check the OMIM text.
KEGG lists the parent entity at H01897. PanelApp Australia lists MOS with biallelic inheritance and a green rating.
Synonyms from the brief: OZEMA20; MOS-related female infertility; MOS-related early embryonic arrest and fragmentation. Orphanet, ICD-11 and MeSH identifiers were not checked.
The data come from aggregated research cohorts of IVF patients with exome sequencing. They do not come from EHR.

2. Etiology

Cause. Biallelic loss-of-function or hypomorphic MOS variants in the woman. Zhang et al. 2021 reported four rare variants in three infertile women with recessive inheritance. The variants were homozygous c.285C>A (p.Asn95Lys), homozygous c.960C>A (p.Cys320Ter), and compound heterozygous c.416T>C (p.Met139Thr) with c.737G>A (p.Arg246His) (Zhang 2021). Zeng et al. 2022 (Hum Reprod) added two families, with p.Asn95Lys and c.467delG (p.Gly156Alafs*18) (OUP). The searches also surfaced a companion paper, "MOS is a novel genetic marker for human early embryonic arrest and fragmentation", which I did not read.
Risk and protective factors. None are documented. No environmental, lifestyle or gene-environment contribution is known. No modifier genes or protective alleles have been reported.

3. Phenotypes

Evidence comes from small case series (about 5 families), so frequencies are not available. Suggested HPO terms need lookup before binding.

Phenotype	Suggested HPO (verify)	Comment
Female infertility	HP:0008222	Primary infertility
Recurrent failed IVF/ICSI cycles	HP:0034210?	Check for a better term
Early embryonic arrest / fragmentation	no precise term likely	Possibly a coarse binding with `NO_HPO_TERM`
Abnormal oocyte morphology or maturation	check the HPO "Abnormal oocyte" subtree

Reported in the summaries: oocytes retrieved and fertilized, with cleavage-stage embryos that arrest and fragment. The summary of the MGI entry mentions amenorrhea as an additional feature in some databases, but I could not verify it. No systemic phenotype is reported. Onset is at the first reproductive attempt. Quality-of-life impact is not studied.

4. Genetic and molecular information

Gene and protein. MOS encodes a serine/threonine kinase (c-Mos, cytostatic factor component) that phosphorylates MEK1 and thereby activates ERK1/2 (MAPK). It is expressed in oocytes.
Variant types. Missense (p.Asn95Lys, p.Met139Thr, p.Arg246His), nonsense (p.Cys320Ter) and frameshift (p.Gly156Alafs*18). All are germline.
Functional consequences. Loss of function. Zeng et al. reported that p.Asn95Lys and the frameshift reduced MOS protein level and that all tested variants reduced the ability of MOS to phosphorylate its downstream target (OUP). Zhang et al. reported reduced ERK1/2 activation (Zhang 2021).
The functional_impact_category is LOSS_OF_FUNCTION or PARTIAL_LOSS_OF_FUNCTION, to be assigned per variant.
gnomAD frequencies and ClinVar classifications were not checked. No ClinGen gene-disease validity record was checked, so run just check-gene-validity. Epigenetic, chromosomal and modifier-gene data are not available.

5. Environmental information

None are reported. There are no infectious agents.

6. Mechanism and pathophysiology

Causal chain (steps 1–5 are demonstrated in human variant assays and cell assays; the later links are partly inferred):

Biallelic germline MOS variants reduce MOS protein level or kinase activity (human variant assays, Zeng 2022).
This leads to reduced MEK–ERK1/2 phosphorylation in the oocyte (human variant assays, Zhang 2021).
This results in defective oocyte cytoplasmic maturation, with impaired meiotic resumption and cytoskeleton assembly defects (described in the search summary; the specific human evidence is not verified).
Maternal mRNA clearance fails during maturation. This was shown in human MII oocytes carrying the MOS variant and in oocytes treated with the MEK inhibitor U0126. The affected transcripts were linked to mitochondrial function (EMBO Mol Med 2021, DOI).
Defective maternal-to-zygotic transition follows, which is inferred. The embryo then arrests at the cleavage stage and fragments.
The clinical result is infertility.

Branch from mouse biology. In the mouse, Mos-null oocytes fail to maintain metaphase II arrest, with spindle abnormalities, a large polar body and parthenogenetic activation. Oocyte-specific Erk1/2 knockout mice reproduce the human EEAF phenotype (search summary). The human phenotype is therefore not a simple MII-arrest failure. The human oocytes of these patients mature to MII and fertilize, so the MII-arrest role in humans is unresolved.

Ontology suggestions (verify each by lookup). GO terms: MAPK cascade (GO:0000165), oocyte maturation (GO:0001556), MAP kinase kinase kinase activity, regulation of mRNA stability, and cytoplasmic mRNA processing. Cell types: oocyte (CL:0000023), zygote (CL:0000365), early embryo blastomere. Anatomy: ovary and embryo.

7. Anatomical structures affected

The ovary (follicle and oocyte) and the preimplantation embryo. The cell types are the oocyte and the cleavage-stage blastomeres. At the subcellular level, the meiotic spindle and cytoskeleton, the cytoplasmic maternal mRNA pool and the mitochondria are affected. The disease is bilateral, with no other organ involved.

8. Temporal development

The condition is congenital genetically but becomes apparent in adulthood, at the first IVF cycle. It is non-progressive and persistent, with no spontaneous remission reported. The critical period is oocyte maturation through the early cleavage stages.

9. Inheritance and population

Autosomal recessive. Both a homozygous and a compound heterozygous genotype are described.
Only women are affected clinically. Male carriers are fertile [unverified].
Prevalence is unknown. About 5 families are known. Zhang 2021 and Zeng 2022 cohorts are East Asian (Chinese), but I did not verify the ancestry. Founder effect and consanguinity were not checked. The source search summaries do not report them.

10. Diagnostics

Genetic testing by exome sequencing or a female-infertility or embryo-arrest gene panel, followed by segregation analysis. MOS is on PanelApp's panel 4455.
Functional confirmation is possible in research settings by testing phospho-ERK1/2 in patient oocytes or in HEK293 cells expressing the variant.
Clinical clues are recurrent EEAF despite normal fertilization and normal semen parameters.
The differential diagnosis includes other genes for embryo arrest (PADI6, TLE6, NLRP5, KHDC3L, PABPC1L, WEE2 for fertilization failure) and non-genetic causes such as sperm factors and culture conditions. Cascade screening of sisters and prenatal or preimplantation testing apply.

11. Outcome and prognosis

Life expectancy is normal. The morbidity is infertility and the psychosocial burden of repeated failed IVF cycles. Spontaneous pregnancy has not been reported. No prognostic factors are known.

12. Treatment

No disease-modifying treatment exists. Repeated conventional IVF/ICSI with the patient's own oocytes does not overcome the arrest.
Practical option: oocyte donation. This is standard for genetically determined oocyte-intrinsic arrest [unverified for MOS specifically].
Experimental: not clinically tested. Possible approaches include ooplasm or mRNA rescue, as the search summary on mechanism suggests; I found no human trial. I found no registered trial (ClinicalTrials.gov not searched).
NCIT suggestions (verify by lookup): assisted reproductive technology / in vitro fertilization, oocyte donation, genetic counseling (NCIT:C15240, listed in the repo guide). Do not infer a therapeutic_modality for these.

13. Prevention

Genetic counseling is the main measure. Carrier testing of at-risk relatives and preimplantation genetic testing for the family variants are possible in principle, though PGT is of limited value when the affected woman's own oocytes arrest. There is no primary prevention.

14. Other species and natural disease

Orthologs exist across vertebrates. Mos is a classic cytostatic factor in Xenopus. No natural veterinary disease was checked (OMIA not searched).

15. Model organisms

Mouse Mos knockout. Females are viable and sterile. Oocytes reach MII but fail to maintain arrest, with spindle abnormalities and parthenogenetic activation. Early reports are Colledge et al. and Hashimoto et al. 1994 (Nature) [unverified, citations not looked up]. The mouse phenotype only partly matches the human one.
Oocyte-specific Erk1/2 knockout mouse. Reproduces the human EEAF phenotype (Zhang 2021). It is the better model of the human mechanism and should be linked with PARTIALLY_RECAPITULATES or RECAPITULATES, with a divergence note.
In vitro. U0126 inhibitor treatment of human oocytes and cell-line assays of the variants. These are IN_VITRO evidence.
The HUMAN_MODEL_MISMATCH discussion kind applies to the MII-arrest difference.

Curation notes and gaps

Fetch and cache the two primary papers (Zhang 2021, Zeng 2022) and the companion paper above with just fetch-reference. Take exact snippets only from the cached bodies.
Look up every CURIE (hgnc, HP, GO, CL, UBERON, NCIT) before binding. Run just check-gene-validity and the GeneReviews check. I found no GeneReviews chapter.
Open questions: the true prevalence, the reason human oocytes mature despite loss of MOS, whether more families exist after 2022, and whether any rescue strategy works.

Sources

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	3
Resolved	1
Unresolved (possible confabulation)	0
Unverifiable	2
References weighed for topical relevance	1
On topic	1
Off topic	0

1 of 3 references resolved; the rest could not be looked up either way.

Term Validation

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

Outcome	Count
Terms checked	9
Resolved	8
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	1
Terms named correctly	1
Terms named as a different term	0

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.

8 of 9 terms resolved to a current term; the rest could not be looked up either way.

MOS-related Oocyte Zygote Embryo Maturation Arrest

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MOS-related Oocyte/Zygote/Embryo Maturation Arrest (OZEMA20): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Curation notes and gaps

Sources

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Term Validation

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