Spermatogenic Failure 68

Mendelian MONDO:0030721 Pathograph 10 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 68 (SPGF68) is autosomal recessive male infertility attributed to biallelic variants in CATSPERT (previously C2CD6, also called ALS2CR11). CATSPERT encodes CatSper tau, a subunit of the sperm-specific CatSper calcium channel. Its C2 membrane-binding domain carries the channel complex into the flagellar membrane and arranges it into four linear calcium signalling nanodomains along the principal piece. The human evidence is a single man. He came from a consanguineous family, had partial globozoospermia, and was homozygous for a missense variant (p.His113Arg) in the C2 domain, classed as of uncertain significance. The mechanism comes from two knockout mouse studies. Without CatSper tau the channel is reduced and the nanodomains are broken up. Sperm still conduct some calcium but cannot hyperactivate and fail to fertilize, while testis histology, sperm counts and sperm morphology stay normal. The human round-headed sperm phenotype and the mouse motility phenotype therefore do not match.

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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE ENDOCRINOLOGY METABOLISM
👪

Inheritance

1
Autosomal recessive HP:0000007
The one reported patient was homozygous for a variant inside a region of homozygosity and was the son of a consanguineous union. Both knockout mouse lines are infertile only when homozygous.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31985809 SUPPORT Human clinical
"In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)"
A homozygous variant in the affected man fits recessive inheritance.
PMID:31985809 SUPPORT Human clinical
"GL-4 | 2 | C2CD6 | Moroccan | Yes (mother is the niece of the father) | 3 brothers and 2 sisters, all fertile"
The patient's parents were related, which is consistent with a recessive allele shared by descent.
?

Discussions and Knowledge Gaps

1
Does loss of CATSPERT cause round-headed sperm in humans, as the one reported patient suggests, or a CatSper hyperactivation defect with normal sperm morphology, as the knockout mice show?
HUMAN MODEL MISMATCH OPEN spgf68_globozoospermia_vs_hyperactivation
Attached to
phenotypes#Globozoospermia pathophysiology#Failure of Sperm Hyperactivation animal_models#CatSpert (C2cd6) loss-of-function mouse
The human evidence is one homozygous missense variant of uncertain significance in a man with partial globozoospermia, found in a cohort selected for that phenotype. Two independent mouse knockouts give a calcium channel targeting and hyperactivation defect with normal sperm heads. These cannot both describe one mechanism. Either the human variant does not cause the patient's globozoospermia, or the human protein has an acrosomal role the mouse does not show. Testing hyperactivation and CatSper current in sperm from men with biallelic CATSPERT variants, and finding further patients, would settle it.
Show evidence (3 references)
PMID:31985809 SUPPORT Human clinical
"Additionally, functional follow-up is needed for several candidate genes to confirm the impact of these mutations on normal spermatogenesis."
The reporting authors state that their candidate genes, C2CD6 among them, have not been confirmed.
PMID:33108537 SUPPORT Human clinical
"searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1)"
A later globozoospermia cohort screened C2CD6 in DPY19L2-negative patients.
PMID:33108537 SUPPORT Human clinical
"Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia."
No C2CD6 variant was found in that screen, so the link between CATSPERT and globozoospermia still rests on the single original patient.
⚙

Pathophysiology

4
Loss of CatSper Tau Membrane-Targeting Function
CatSper tau is a CatSper channel subunit with a calcium-dependent C2 membrane-binding domain. It reaches the flagellum on its own and acts as the main component that targets the channel complex to the flagellar membrane. It is not needed to assemble a working channel. In mice, truncating the C2 domain was enough to stop the channel being carried into the nanodomains of developing spermatids. The human variant p.His113Arg lies in the same C2 domain, but its effect on the protein has not been tested.
spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology. sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
CATSPERT hgnc:14438 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CATSPERT, annotated with C2CD6 (hgnc:14438). hgnc:14438 is a gene from the HUGO Gene Nomenclature Committee.
CatSper complex GO:0036128 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves CatSper complex (GO:0036128). GO:0036128 is a protein complex from the Gene Ontology.
protein localization to the flagellar (ciliary) membrane GO:1903441 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to the flagellar (ciliary) membrane, annotated with protein localization to ciliary membrane (GO:1903441). GO:1903441 is a biological process from the Gene Ontology.
membrane targeting of the CatSper channel complex GO:0043495 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased membrane targeting of the CatSper channel complex, annotated with protein-membrane adaptor activity (GO:0043495). GO:0043495 is a molecular function from the Gene Ontology.
sperm flagellum GO:0036126 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sperm flagellum (GO:0036126). GO:0036126 is a cellular component from the Gene Ontology.
testis UBERON:0000473 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in testis (UBERON:0000473). UBERON:0000473 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Disrupted CatSper Nanodomains in the Sperm Flagellum Without the targeting subunit, the channel that reaches the flagellum is reduced and does not form the four continuous linear domains.
Show evidence (5 references)
PMID:34998468 SUPPORT Model organism
"Here, we report CatSperτ, the C2cd6-encoded membrane-associating C2 domain protein, can independently migrate to the flagella and serve as a major targeting component of the CatSper channel complex."
Defines CatSper tau as the subunit that targets the channel to the flagellum.
PMID:34998468 SUPPORT Model organism
"C2 domain truncation of CatSperτ is sufficient to compromise the spatiotemporal trafficking of the CatSper channel into the nanodomains in developing spermatids."
Shows that the C2 domain is required for the targeting function, which is where the human variant lies.
PMID:34919125 SUPPORT Model organism
"C2CD6 associates with the CatSper calcium-selective, core-forming subunits."
Places C2CD6 in the CatSper complex with the pore-forming subunits.
+ 2 more references
Disrupted CatSper Nanodomains in the Sperm Flagellum
In mouse knockout sperm the CatSper channel shows two or three discontinuous lines instead of four continuous ones along the principal piece, and the amount of channel is lower. A smaller CatSper current remains.
sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
sperm flagellum GO:0036126 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sperm flagellum (GO:0036126). GO:0036126 is a cellular component from the Gene Ontology.
Downstream
Insufficient Flagellar Calcium Entry During Capacitation Fewer and disorganized channels conduct less calcium into the flagellum.
Show evidence (1 reference)
PMID:34998468 SUPPORT Model organism
"First, the CatSper channel presented only two or three discontinuous linear nanodomains"
Describes the broken nanodomain pattern in mutant sperm.
Insufficient Flagellar Calcium Entry During Capacitation
Mutant mouse sperm still form a working CatSper channel and conduct calcium, but not enough to drive hyperactivated motility.
sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
calcium ion import across plasma membrane GO:0098703 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased calcium ion import across plasma membrane (GO:0098703). GO:0098703 is a biological process from the Gene Ontology.
calcium channel activity GO:0005262 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased calcium channel activity (GO:0005262). GO:0005262 is a molecular function from the Gene Ontology.
Downstream
Failure of Sperm Hyperactivation Hyperactivated motility needs calcium entry through CatSper. Raising intracellular calcium with an ionophore restored fertilizing capacity to knockout sperm, which places the block at calcium entry.
Show evidence (1 reference)
PMID:34998468 SUPPORT Model organism
"Intriguingly, Ca2+ conductance in CatSpertΔ/Δ sperm was not enough to develop hyperactivated motility"
Calcium conduction is present but below what hyperactivation needs.
Failure of Sperm Hyperactivation
Under capacitating conditions, knockout mouse sperm do not switch to the slow, asymmetric, high-amplitude beat of hyperactivated motility. They fail to fertilize oocytes in vitro and in vivo.
sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
sperm capacitation GO:0048240 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sperm capacitation (GO:0048240). GO:0048240 is a biological process from the Gene Ontology. flagellated sperm motility GO:0030317 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased flagellated sperm motility (GO:0030317). GO:0030317 is a biological process from the Gene Ontology.
Animal models
CatSpert (C2cd6) loss-of-function mouse Mouse recapitulates Mutant sperm do not hyperactivate and do not fertilize oocytes.
Downstream
Male infertility Sperm that cannot hyperactivate do not fertilize, so males are sterile despite normal sperm production.
Show evidence (1 reference)
PMID:34998468 SUPPORT Model organism
"All the results demonstrate that CatSperτ loss of function impairs hyperactivated motility and causes male infertility."
Summarizes the motility analysis in the knockout.
⬡

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 Spermatogenic Failure 68 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

2
Male infertility Reproductive HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31985809 SUPPORT Human clinical
"exome sequencing was performed in 15 males with globozoospermia or acrosomal hypoplasia of unknown aetiology"
The patient was ascertained in an infertility cohort.
PMID:31985809 SUPPORT BACKGROUND Human clinical
"Globozoospermia is a rare form of male infertility characterised by round-headed sperm and malformation of the acrosome."
States that globozoospermia, the phenotype of the reported patient, is a form of male infertility.
PMID:34998468 SUPPORT Model organism
"CatSperτ loss of function in mice demonstrates that it is essential for sperm hyperactivated motility and male fertility."
Knockout males are infertile.
Globozoospermia Reproductive HP:0012205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Partial globozoospermia, annotated with Globozoospermia (HP:0012205). HP:0012205 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31985809 SUPPORT Human clinical
"GL-4 | 2 | C2CD6 | Moroccan | Yes (mother is the niece of the father) | 3 brothers and 2 sisters, all fertile"
The globozoospermia type column records type 2 (partial) globozoospermia for the C2CD6 patient.
PMID:34998468 REFUTE INDIRECT Model organism
"despite normal testis histology, sperm morphology, and sperm counts in cauda epididymis"
Knockout mouse sperm have normal morphology, which does not support loss of CatSper tau as a cause of round-headed sperm.
🧬

Genetic Associations

1
CATSPERT
Gene: CATSPERT hgnc:14438 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CATSPERT, annotated with C2CD6 (hgnc:14438). hgnc:14438 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal recessive
Show evidence (2 references)
PMID:31985809 SUPPORT Human clinical
"GL-4 | C2CD6 (ALS2CR11) | p.(His113Arg) | Homozygous | Absent | Uncertain significance | No | Yes (Wang et al. 2015) | Possibly causative"
The only human variant, graded by its authors as possibly causative and of uncertain significance.
PMID:34919125 SUPPORT Model organism
"Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility."
Loss of the mouse orthologue causes male sterility.
Variants (1)
c.338A>G (p.His113Arg) Uncertain significance
single nucleotide variant
Genomic context: coding sequence
Homozygous missense variant in the conserved C2 membrane-binding domain of CATSPERT (C2CD6), identified in a single Moroccan patient with partial (type 2) globozoospermia and classified as a variant of uncertain significance.
Show evidence (1 reference)
PMID:31985809 SUPPORT Human clinical
"In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)"
Documents the homozygous c.338A>G (p.His113Arg) missense variant in patient GL-4.
💊

Medical Actions

2
Intracytoplasmic Sperm Injection (ICSI)
Category: Therapeutic Action: Intracytoplasmic Sperm InjectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intracytoplasmic Sperm Injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. NCIT:C185482
Platform: Other
Intracytoplasmic sperm injection (ICSI) places a single spermatozoon directly into the oocyte, so fertilisation no longer depends on hyperactivated motility or zona pellucida penetration. Men with type I globozoospermia who wish to conceive must use ICSI, but fertilisation rates with ICSI in globozoospermia are much lower than in other male infertility, and assisted oocyte activation (AOA) is reported to restore them. No ICSI outcome has been reported for a CATSPERT patient.
Mechanism Target:
BYPASSES Failure of Sperm Hyperactivation — Direct injection of a single spermatozoon into the oocyte cytoplasm bypasses the requirement for CatSper-mediated hyperactivated motility and zona pellucida penetration.
Show evidence (1 reference)
PMID:34998468 SUPPORT INDIRECT Model organism
"Therefore, the levels of CatSper proteins and/or ICatSper can serve as a prognosis to determine clinical approaches; i.e., in vitro fertilization (IVF) versus intracytoplasmic sperm injection (ICSI)."
The authors' clinical inference from their knockout-mouse results, not an experiment. It proposes choosing ICSI over IVF when CatSper is deficient, which implies that ICSI avoids the hyperactivation requirement, but no ICSI was performed with CatSpert-deficient sperm.
Target Phenotypes: Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:31985809 SUPPORT Human clinical
"Patients with globozoospermia type I and wishing to conceive are forced to use ICSI for fertilisation."
Establishes ICSI as the assisted reproductive intervention required for fertilization in men with type I globozoospermia.
PMID:31985809 SUPPORT BACKGROUND Human clinical
"The success rate of fertilisation using ICSI for globozoospermic men is however lower than in unselected groups of male infertility (24.3% compared to 70–80%), and rates range between 0 and 100%, with most authors reporting low to no fertilisation"
Qualifies the treatment claim. ICSI is required but often fails in globozoospermia; the figures are cited from earlier clinical series rather than measured in this study.
PMID:31985809 SUPPORT BACKGROUND Human clinical
"The fertilisation rate is restored by assisted oocyte activation (AOA) using mechanical, chemical and electrical approaches"
Assisted oocyte activation alongside ICSI is reported to restore fertilisation in globozoospermia, cited from earlier work.
+ 1 more reference
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic and reproductive counseling regarding autosomal recessive inheritance and the outcomes and risks of assisted reproductive treatments such as ICSI.
Show evidence (1 reference)
PMID:31985809 SUPPORT Human clinical
"Elucidating the genetic cause of globozoospermia can help to better understand the aetiology of globozoospermia, which is invaluable to better understand the process of spermiogenesis and to predict the success as well as the risks of reproductive treatments such as ICSI."
Genetic diagnosis informs reproductive counseling on the success and risks of ICSI.
🔬

Diagnosis

2
Semen Analysis
Microscopic evaluation of sperm concentration, motility, and morphology to identify round-headed spermatozoa (globozoospermia) or impaired motility in infertile men.
Results: Partial (type 2) globozoospermia reported in the single described human patient.
Show evidence (1 reference)
PMID:31985809 SUPPORT Human clinical
"For each of the 16 men, semen analysis to assess sperm concentration and sperm morphology was performed by the IVF clinics treating the patients."
Semen analysis was used to evaluate sperm concentration and morphology in the diagnostic workup of infertile patients.
Whole Exome Sequencing
Exome sequencing with homozygosity mapping to detect biallelic variants in CATSPERT (C2CD6) after excluding common causes of globozoospermia such as DPY19L2 deletions.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: A homozygous missense variant in CATSPERT (C2CD6) in the single reported patient.
Show evidence (1 reference)
PMID:31985809 SUPPORT Human clinical
"In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)"
Exome sequencing identified the homozygous C2CD6 variant in patient GL-4.
⚖️

Clinical Burden

Low
The effect is reproductive only. No systemic features have been reported in the patient or in knockout mice.
🐁

Animal Models

1
CatSpert (C2cd6) loss-of-function mouse
Two groups made knockout lines independently (PMID:34998468, PMID:34919125). Homozygous males are sterile with normal testis histology, sperm counts and sperm morphology.
Species
Mouse
Genotype
CatSpert (C2cd6) null and C2-domain-truncating alleles, homozygous
Publication
PMID:34998468
Pathograph links
Failure of Sperm Hyperactivation recapitulates fidelity: unknown observes: cellular Mutant sperm do not hyperactivate and do not fertilize oocytes.
Limitations: No human sperm carrying a CATSPERT variant has been tested for hyperactivation or CatSper current, so whether the human disease works through this step is not known.
Show evidence (1 reference)
PMID:34919125 SUPPORT Model organism
"C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo."
The knockout reproduces the motility and fertilization failure.
{ }

Source YAML

click to show 
name: Spermatogenic Failure 68
creation_date: '2026-10-22T00:00:00Z'
category: Mendelian
synonyms:
- SPGF68
- spermatogenic failure 68
- CATSPERT-related male infertility
- C2CD6-related male infertility
description: 'Spermatogenic failure 68 (SPGF68) is autosomal recessive male infertility attributed to
  biallelic variants in CATSPERT (previously C2CD6, also called ALS2CR11). CATSPERT encodes CatSper tau,
  a subunit of the sperm-specific CatSper calcium channel. Its C2 membrane-binding domain carries the
  channel complex into the flagellar membrane and arranges it into four linear calcium signalling nanodomains
  along the principal piece.

  The human evidence is a single man. He came from a consanguineous family, had partial globozoospermia,
  and was homozygous for a missense variant (p.His113Arg) in the C2 domain, classed as of uncertain significance.
  The mechanism comes from two knockout mouse studies. Without CatSper tau the channel is reduced and
  the nanodomains are broken up. Sperm still conduct some calcium but cannot hyperactivate and fail to
  fertilize, while testis histology, sperm counts and sperm morphology stay normal. The human round-headed
  sperm phenotype and the mouse motility phenotype therefore do not match.'
disease_term:
  preferred_term: spermatogenic failure 68
  term:
    id: MONDO:0030721
    label: spermatogenic failure 68
parents:
- Spermatogenic Failure
- Genetic Disease
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:31985809
      reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human
        globozoospermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in
        C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)
      explanation: Supports classification as a heritable autosomal recessive genetic disorder.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:31985809
      reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human
        globozoospermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Globozoospermia is a rare form of male infertility characterised by round-headed sperm
        and malformation of the acrosome.
      explanation: Supports classification under reproductive endocrinology and male infertility disorders.
      quote_role: BACKGROUND
notes: MONDO cross-references this disease as OMIM 619805 and records CATSPERT as its causal gene, with
  no descendant terms. A PubMed search for CATSPERT, C2CD6, ALS2CR11, TMEM249 and CatSper tau on 2026-10-22
  found one human report (PMID:31985809, patient GL-4) and the mouse knockout studies cited here. A later
  globozoospermia cohort screened C2CD6 in 23 DPY19L2-negative patients and found no candidate variant
  (PMID:33108537). The deep-research report in research/ also found no further patients, and no functional
  test of p.His113Arg. TMEM249, sometimes named as a further CatSper component, is a separate gene and
  not part of this entry.
inheritance:
- name: Autosomal recessive
  description: The one reported patient was homozygous for a variant inside a region of homozygosity and
    was the son of a consanguineous union. Both knockout mouse lines are infertile only when homozygous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in C2
      calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)
    explanation: A homozygous variant in the affected man fits recessive inheritance.
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GL-4 | 2 | C2CD6 | Moroccan | Yes (mother is the niece of the father) | 3 brothers and 2
      sisters, all fertile
    explanation: The patient's parents were related, which is consistent with a recessive allele shared
      by descent.
pathophysiology:
- name: Loss of CatSper Tau Membrane-Targeting Function
  description: CatSper tau is a CatSper channel subunit with a calcium-dependent C2 membrane-binding domain.
    It reaches the flagellum on its own and acts as the main component that targets the channel complex
    to the flagellar membrane. It is not needed to assemble a working channel. In mice, truncating the
    C2 domain was enough to stop the channel being carried into the nanodomains of developing spermatids.
    The human variant p.His113Arg lies in the same C2 domain, but its effect on the protein has not been
    tested.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  cellular_components:
  - preferred_term: sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  genes:
  - preferred_term: CATSPERT
    term:
      id: hgnc:14438
      label: C2CD6
  protein_complexes:
  - preferred_term: CatSper complex
    term:
      id: GO:0036128
      label: CatSper complex
  molecular_functions:
  - preferred_term: membrane targeting of the CatSper channel complex
    modifier: DECREASED
    term:
      id: GO:0043495
      label: protein-membrane adaptor activity
  biological_processes:
  - preferred_term: protein localization to the flagellar (ciliary) membrane
    modifier: DECREASED
    term:
      id: GO:1903441
      label: protein localization to ciliary membrane
  downstream:
  - target: Disrupted CatSper Nanodomains in the Sperm Flagellum
    causal_link_type: DIRECT
    description: Without the targeting subunit, the channel that reaches the flagellum is reduced and
      does not form the four continuous linear domains.
    evidence:
    - reference: PMID:34998468
      reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
        in the flagellar membrane.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: CatSperτ targets the CatSper channel into the quadrilinear nanodomains in the flagella
        of developing spermatids, whereas it is dispensable for functional channel assembly.
      explanation: Places CatSper tau upstream of nanodomain organization in mouse spermatids.
    - reference: PMID:34919125
      reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
        in sperm flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in
        male sterility.
      explanation: An independent knockout gives the same loss of flagellar nanodomains.
  evidence:
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we report CatSperτ, the C2cd6-encoded membrane-associating C2 domain protein, can independently
      migrate to the flagella and serve as a major targeting component of the CatSper channel complex.
    explanation: Defines CatSper tau as the subunit that targets the channel to the flagellum.
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: C2 domain truncation of CatSperτ is sufficient to compromise the spatiotemporal trafficking
      of the CatSper channel into the nanodomains in developing spermatids.
    explanation: Shows that the C2 domain is required for the targeting function, which is where the human
      variant lies.
  - reference: PMID:34919125
    reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
      in sperm flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: C2CD6 associates with the CatSper calcium-selective, core-forming subunits.
    explanation: Places C2CD6 in the CatSper complex with the pore-forming subunits.
  - reference: PMID:34919125
    reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
      in sperm flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: C2CD6 contains a calcium-dependent, membrane-targeting C2 domain.
    explanation: With the binding to the core subunits above, this is the protein-membrane adaptor activity
      bound on this node.
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The missense variant is located in the conserved C2 domain (InterPro: IPR000008) which has
      an important function in calcium-dependent phospholipid binding and targeting proteins to cell membranes'
    explanation: Places the human variant in the domain the mouse work shows is needed for targeting;
      the variant's own effect was not measured.
- name: Disrupted CatSper Nanodomains in the Sperm Flagellum
  description: In mouse knockout sperm the CatSper channel shows two or three discontinuous lines instead
    of four continuous ones along the principal piece, and the amount of channel is lower. A smaller CatSper
    current remains.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  downstream:
  - target: Insufficient Flagellar Calcium Entry During Capacitation
    causal_link_type: DIRECT
    description: Fewer and disorganized channels conduct less calcium into the flagellum.
    evidence:
    - reference: PMID:34919125
      reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
        in sperm flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: CatSper currents are present but at a significantly lower level in C2CD6-deficient sperm.
      explanation: Measures the reduced CatSper current that follows nanodomain loss.
  evidence:
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: First, the CatSper channel presented only two or three discontinuous linear nanodomains
    explanation: Describes the broken nanodomain pattern in mutant sperm.
- name: Insufficient Flagellar Calcium Entry During Capacitation
  description: Mutant mouse sperm still form a working CatSper channel and conduct calcium, but not enough
    to drive hyperactivated motility.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: calcium ion import across plasma membrane
    modifier: DECREASED
    term:
      id: GO:0098703
      label: calcium ion import across plasma membrane
  molecular_functions:
  - preferred_term: calcium channel activity
    modifier: DECREASED
    term:
      id: GO:0005262
      label: calcium channel activity
  downstream:
  - target: Failure of Sperm Hyperactivation
    causal_link_type: DIRECT
    description: Hyperactivated motility needs calcium entry through CatSper. Raising intracellular calcium
      with an ionophore restored fertilizing capacity to knockout sperm, which places the block at calcium
      entry.
    evidence:
    - reference: PMID:34998468
      reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
        in the flagellar membrane.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We demonstrate that mutant sperm still form the functional CatSper channel, albeit significantly
        decreased, and conduct calcium, but they fail to hyperactivate, rendering the male infertile.
      explanation: Links the reduced channel and calcium conduction to failed hyperactivation.
    - reference: PMID:34919125
      reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
        in sperm flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore
        the fertilization capacity of C2CD6-deficient sperm.
      explanation: Bypassing the calcium entry defect rescues fertilization, so the defect lies upstream
        of hyperactivation.
  evidence:
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Intriguingly, Ca2+ conductance in CatSpertΔ/Δ sperm was not enough to develop hyperactivated
      motility
    explanation: Calcium conduction is present but below what hyperactivation needs.
- name: Failure of Sperm Hyperactivation
  description: Under capacitating conditions, knockout mouse sperm do not switch to the slow, asymmetric,
    high-amplitude beat of hyperactivated motility. They fail to fertilize oocytes in vitro and in vivo.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: sperm capacitation
    modifier: DECREASED
    term:
      id: GO:0048240
      label: sperm capacitation
  - preferred_term: flagellated sperm motility
    modifier: DECREASED
    term:
      id: GO:0030317
      label: flagellated sperm motility
  downstream:
  - target: Male infertility
    causal_link_type: DIRECT
    description: Sperm that cannot hyperactivate do not fertilize, so males are sterile despite normal
      sperm production.
    evidence:
    - reference: PMID:34919125
      reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
        in sperm flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both
        in vitro and in vivo.
      explanation: Connects failed hyperactivation to failed fertilization.
  evidence:
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: All the results demonstrate that CatSperτ loss of function impairs hyperactivated motility
      and causes male infertility.
    explanation: Summarizes the motility analysis in the knockout.
phenotypes:
- category: Reproductive
  name: Male infertility
  diagnostic: true
  description: Primary male infertility. In the reported man no ICSI was attempted. In knockout mice,
    males mate normally but sire no litters.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: exome sequencing was performed in 15 males with globozoospermia or acrosomal hypoplasia of
      unknown aetiology
    explanation: The patient was ascertained in an infertility cohort.
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: Globozoospermia is a rare form of male infertility characterised by round-headed sperm and
      malformation of the acrosome.
    explanation: States that globozoospermia, the phenotype of the reported patient, is a form of male
      infertility.
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CatSperτ loss of function in mice demonstrates that it is essential for sperm hyperactivated
      motility and male fertility.
    explanation: Knockout males are infertile.
- category: Reproductive
  name: Globozoospermia
  description: Round-headed sperm lacking an acrosome. The one reported man had partial (type 2) globozoospermia.
    This is not seen in knockout mice, whose sperm have normal morphology, so whether the human variant
    explains it is unsettled.
  phenotype_term:
    preferred_term: Partial globozoospermia
    term:
      id: HP:0012205
      label: Globozoospermia
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GL-4 | 2 | C2CD6 | Moroccan | Yes (mother is the niece of the father) | 3 brothers and 2
      sisters, all fertile
    explanation: The globozoospermia type column records type 2 (partial) globozoospermia for the C2CD6
      patient.
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: despite normal testis histology, sperm morphology, and sperm counts in cauda epididymis
    explanation: Knockout mouse sperm have normal morphology, which does not support loss of CatSper tau
      as a cause of round-headed sperm.
genetic:
- name: CATSPERT
  notes: CATSPERT was previously named C2CD6 and ALS2CR11; the HGNC build used for term validation still
    gives C2CD6 as the label of hgnc:14438. The one reported human allele is c.338A>G p.(His113Arg), homozygous,
    absent from gnomAD and classed as of uncertain significance under ACMG/AMP criteria by the reporting
    authors, who called it possibly causative. Their link to acrosome biology rested on protein interactions
    with SPATA16 and ZPBP. Mouse loss-of-function alleles (exon deletions and a C2-domain truncation)
    cause infertility through the CatSper channel instead. CAUSATIVE here follows the disease definition,
    which MONDO and OMIM key on this gene; it does not reflect the strength of the human evidence, which
    is one variant of uncertain significance.
  gene_term:
    preferred_term: CATSPERT
    term:
      id: hgnc:14438
      label: C2CD6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:31985809
      reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human
        globozoospermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in
        C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)
      explanation: Homozygous variant in an affected male from a consanguineous union supports autosomal
        recessive inheritance.
  variants:
  - name: c.338A>G (p.His113Arg)
    description: Homozygous missense variant in the conserved C2 membrane-binding domain of CATSPERT (C2CD6),
      identified in a single Moroccan patient with partial (type 2) globozoospermia and classified as
      a variant of uncertain significance.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    variant_type: single nucleotide variant
    genomic_contexts:
    - coding sequence
    evidence:
    - reference: PMID:31985809
      reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human
        globozoospermia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in
        C2 calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)
      explanation: Documents the homozygous c.338A>G (p.His113Arg) missense variant in patient GL-4.
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GL-4 | C2CD6 (ALS2CR11) | p.(His113Arg) | Homozygous | Absent | Uncertain significance |
      No | Yes (Wang et al. 2015) | Possibly causative
    explanation: The only human variant, graded by its authors as possibly causative and of uncertain
      significance.
  - reference: PMID:34919125
    reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
      in sperm flagella.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male
      sterility.
    explanation: Loss of the mouse orthologue causes male sterility.
diagnosis:
- name: Semen Analysis
  description: Microscopic evaluation of sperm concentration, motility, and morphology to identify round-headed
    spermatozoa (globozoospermia) or impaired motility in infertile men.
  results: Partial (type 2) globozoospermia reported in the single described human patient.
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For each of the 16 men, semen analysis to assess sperm concentration and sperm morphology
      was performed by the IVF clinics treating the patients.
    explanation: Semen analysis was used to evaluate sperm concentration and morphology in the diagnostic
      workup of infertile patients.
- name: Whole Exome Sequencing
  description: Exome sequencing with homozygosity mapping to detect biallelic variants in CATSPERT (C2CD6)
    after excluding common causes of globozoospermia such as DPY19L2 deletions.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: A homozygous missense variant in CATSPERT (C2CD6) in the single reported patient.
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In patient GL-4, a homozygous missense variant (c.338A > G; p.(His113Arg)) was found in C2
      calcium-dependent domain-containing 6 (C2CD6, also known as ALS2CR11)
    explanation: Exome sequencing identified the homozygous C2CD6 variant in patient GL-4.
treatments:
- name: Intracytoplasmic Sperm Injection (ICSI)
  description: Intracytoplasmic sperm injection (ICSI) places a single spermatozoon directly into the
    oocyte, so fertilisation no longer depends on hyperactivated motility or zona pellucida penetration.
    Men with type I globozoospermia who wish to conceive must use ICSI, but fertilisation rates with ICSI
    in globozoospermia are much lower than in other male infertility, and assisted oocyte activation
    (AOA) is reported to restore them. No ICSI outcome has been reported for a CATSPERT patient.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Failure of Sperm Hyperactivation
    treatment_effect: BYPASSES
    description: Direct injection of a single spermatozoon into the oocyte cytoplasm bypasses the requirement
      for CatSper-mediated hyperactivated motility and zona pellucida penetration.
    evidence:
    - reference: PMID:34998468
      reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
        in the flagellar membrane.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: Therefore, the levels of CatSper proteins and/or ICatSper can serve as a prognosis to determine
        clinical approaches; i.e., in vitro fertilization (IVF) versus intracytoplasmic sperm injection
        (ICSI).
      explanation: The authors' clinical inference from their knockout-mouse results, not an experiment.
        It proposes choosing ICSI over IVF when CatSper is deficient, which implies that ICSI avoids the
        hyperactivation requirement, but no ICSI was performed with CatSpert-deficient sperm.
  target_phenotypes:
  - preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with globozoospermia type I and wishing to conceive are forced to use ICSI for fertilisation.
    explanation: Establishes ICSI as the assisted reproductive intervention required for fertilization
      in men with type I globozoospermia.
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: The success rate of fertilisation using ICSI for globozoospermic men is however lower than in
      unselected groups of male infertility (24.3% compared to 70–80%), and rates range between 0 and 100%,
      with most authors reporting low to no fertilisation
    explanation: Qualifies the treatment claim. ICSI is required but often fails in globozoospermia; the
      figures are cited from earlier clinical series rather than measured in this study.
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: The fertilisation rate is restored by assisted oocyte activation (AOA) using mechanical, chemical
      and electrical approaches
    explanation: Assisted oocyte activation alongside ICSI is reported to restore fertilisation in globozoospermia,
      cited from earlier work.
  - reference: PMID:34998468
    reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
      in the flagellar membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Therefore, the levels of CatSper proteins and/or ICatSper can serve as a prognosis to determine
      clinical approaches; i.e., in vitro fertilization (IVF) versus intracytoplasmic sperm injection
      (ICSI).
    directness: INDIRECT
    explanation: The authors' clinical inference from knockout-mouse results, proposing ICSI rather than
      IVF when CatSper levels or currents are reduced. No ICSI was performed in the study.
- name: Genetic Counseling
  description: Genetic and reproductive counseling regarding autosomal recessive inheritance and the outcomes
    and risks of assisted reproductive treatments such as ICSI.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Elucidating the genetic cause of globozoospermia can help to better understand the aetiology
      of globozoospermia, which is invaluable to better understand the process of spermiogenesis and to
      predict the success as well as the risks of reproductive treatments such as ICSI.
    explanation: Genetic diagnosis informs reproductive counseling on the success and risks of ICSI.
animal_models:
- name: CatSpert (C2cd6) loss-of-function mouse
  species: Mouse
  genotype: CatSpert (C2cd6) null and C2-domain-truncating alleles, homozygous
  publication: PMID:34998468
  description: Two groups made knockout lines independently (PMID:34998468, PMID:34919125). Homozygous
    males are sterile with normal testis histology, sperm counts and sperm morphology.
  modeled_mechanisms:
  - target: Failure of Sperm Hyperactivation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: Mutant sperm do not hyperactivate and do not fertilize oocytes.
    limitations: No human sperm carrying a CATSPERT variant has been tested for hyperactivation or CatSper
      current, so whether the human disease works through this step is not known.
    evidence:
    - reference: PMID:34919125
      reference_title: C2CD6 regulates targeting and organization of the CatSper calcium channel complex
        in sperm flagella.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both
        in vitro and in vivo.
      explanation: The knockout reproduces the motility and fertilization failure.
  - target: Globozoospermia
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: The human patient had round-headed sperm; knockout mouse sperm look normal.
    limitations: The mouse alleles remove the protein or its C2 domain, while the human allele is a single
      missense change, and the human case may carry a second, undetected cause of globozoospermia.
    evidence:
    - reference: PMID:34998468
      reference_title: C2cd6-encoded CatSperτ targets sperm calcium channel to Ca(2+) signaling domains
        in the flagellar membrane.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: despite normal testis histology, sperm morphology, and sperm counts in cauda epididymis
      explanation: Knockout sperm morphology is normal.
discussions:
- discussion_id: spgf68_globozoospermia_vs_hyperactivation
  prompt: Does loss of CATSPERT cause round-headed sperm in humans, as the one reported patient suggests,
    or a CatSper hyperactivation defect with normal sperm morphology, as the knockout mice show?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - phenotypes#Globozoospermia
  - pathophysiology#Failure of Sperm Hyperactivation
  - animal_models#CatSpert (C2cd6) loss-of-function mouse
  rationale: The human evidence is one homozygous missense variant of uncertain significance in a man
    with partial globozoospermia, found in a cohort selected for that phenotype. Two independent mouse
    knockouts give a calcium channel targeting and hyperactivation defect with normal sperm heads. These
    cannot both describe one mechanism. Either the human variant does not cause the patient's globozoospermia,
    or the human protein has an acrosomal role the mouse does not show. Testing hyperactivation and CatSper
    current in sperm from men with biallelic CATSPERT variants, and finding further patients, would settle
    it.
  evidence:
  - reference: PMID:31985809
    reference_title: Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, functional follow-up is needed for several candidate genes to confirm the impact
      of these mutations on normal spermatogenesis.
    explanation: The reporting authors state that their candidate genes, C2CD6 among them, have not been
      confirmed.
  - reference: PMID:33108537
    reference_title: Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2
      still the main actor, GGN confirmed as a guest player.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: searching for deleterious variants in the nine other genes described to be associated with
      globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1)
    explanation: A later globozoospermia cohort screened C2CD6 in DPY19L2-negative patients.
  - reference: PMID:33108537
    reference_title: Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2
      still the main actor, GGN confirmed as a guest player.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only one homozygous novel truncating variant was identified in the GGN gene in one patient,
      confirming the association of GGN with globozoospermia.
    explanation: No C2CD6 variant was found in that screen, so the link between CATSPERT and globozoospermia
      still rests on the single original patient.
clinical_burden:
  burden_level: LOW
  rationale: The effect is reproductive only. No systemic features have been reported in the patient or
    in knockout mice.
📚

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)

Record notes

MONDO cross-references this disease as OMIM 619805 and records CATSPERT as its causal gene, with no descendant terms. A PubMed search for CATSPERT, C2CD6, ALS2CR11, TMEM249 and CatSper tau on 2026-10-22 found one human report (PMID:31985809, patient GL-4) and the mouse knockout studies cited here. A later globozoospermia cohort screened C2CD6 in 23 DPY19L2-negative patients and found no candidate variant (PMID:33108537). The deep-research report in research/ also found no further patients, and no functional test of p.His113Arg. TMEM249, sometimes named as a further CatSper component, is a separate gene and not part of this entry.

Claude Code ▸
Spermatogenic Failure 68 (SPGF68; MONDO:0030721; OMIM:619805): CATSPERT-related globozoospermia
claude-haiku-5-5, claude-sonnet-5-5 17 citations 2026-10-23T21:13:36.731958

Still working: I'm looking up PMIDs for the key papers on Europe PMC, then I'll write the report.

Spermatogenic Failure 68 (SPGF68; MONDO:0030721; OMIM:619805): CATSPERT-related globozoospermia

Reliability. The human evidence for this disease is a single reported patient. I verified the mouse biology from search-result abstracts and snippets. I could not open OMIM, GeneCards or PubMed directly, because the proxy refused those connections. Quotes below are paraphrases of search-result text, not verified abstract quotes. Before any quote goes into a snippet, run just fetch-reference and check it against the cache. I did not confirm the PMID for Oud et al. 2020. I did not verify MONDO, HGNC, HPO, GO or UBERON identifiers, so look each one up before binding it.

1. Disease information

SPGF68 is an autosomal recessive male infertility disorder. It is caused by a homozygous missense variant in CATSPERT, the gene whose older symbols are C2CD6 and ALS2CR11. The gene encodes CatSperτ (tau), an auxiliary subunit of the sperm CatSper calcium channel. OMIM's gene entry is *619776 (C2CD6) (OMIM). The phenotype entry is #619805.

  • Phenotype: normal sperm count but globozoospermia. The sperm are round-headed and lack an acrosome. Some patients have a mix of acrosomeless sperm and sperm with a small or detached acrosome (acrosomal hypoplasia) (MalaCards, GeneCards).
  • Evidence base: OMIM and the Disease Ontology rest this entry on one Moroccan man. The Disease Ontology notes only one patient as of 2024. A 2025 Tunisian globozoospermia study lists C2CD6 only as a candidate gene needing functional confirmation (Springer).
  • Synonym: SPGF68. A related GeneCards disease label is "male infertility due to globozoospermia".
  • Data source: this is aggregated disease-level information. It does not come from EHR data.
  • Naming trap: the SPGF serial number does not say which gene is involved, and this gene is not one of the other CATSPER genes. CATSPER1 and CATSPER2 variants cause different entries, such as CATSPER1-related nonsyndromic male infertility and the deafness-infertility syndrome from a CATSPER2–STRC deletion. They are not SPGF68 (MedlinePlus). Also keep it apart from the CATSPERθ (CATSPERTHETA) work (PNAS 2023, PMID 37725640).

2. Etiology

  • Cause: a homozygous germline variant in CATSPERT/C2CD6 (human genomic location 2q33.1).
  • Genetic risk and protective factors, and gene–environment interaction: none reported.
  • Environmental factors: none reported for this entry.

3. Phenotypes

The report rests on one patient, so there are no frequencies. HPO suggestions (look each up before binding):

Phenotype Type Suggested HPO term
Male infertility Clinical Male infertility (HP:0003251)
Globozoospermia (round-headed, acrosomeless sperm) Laboratory (semen analysis) Globozoospermia (HP:0034307)
Acrosomal hypoplasia in some sperm Laboratory Look up
Normal sperm count Laboratory Not applicable (a normal finding)
  • Onset and course: onset is adult, at the age of attempted conception. Severity is infertility. The disorder is not progressive. No syndromic features are reported.
  • Quality of life: not reported.

4. Genetic and molecular information

  • Gene: CATSPERT (HGNC lowercase form in the KB; look up the ID). Old symbols are C2CD6 and ALS2CR11.
  • Variant: NM_001168221.2:c.338A>G, p.His113Arg (H113R). It is homozygous and missense. ClinVar variation ID 1345025 (ClinVar).
  • Site and frequency: the histidine is conserved, in the C2 domain. The variant is absent from gnomAD.
  • Discovery: exome sequencing of a globozoospermia cohort (Oud et al., Hum Reprod 2020; 35(1):240–252, OUP).
  • Segregation: not reported.
  • Origin: germline.
  • Mechanism class: presumed loss of function. This is an inference from the mouse knockout, not demonstrated for H113R. No functional study of H113R is known to me.
  • Modifier genes, epigenetic changes, chromosomal abnormalities: none reported.

5. Environmental information

None reported. There are no infectious agents and no lifestyle factors.

6. Mechanism and pathophysiology

Causal chain (steps 3 to 6 come from mouse data, and step 2 is inferred):

  1. A homozygous CATSPERT c.338A>G (p.His113Arg) variant changes a conserved residue in the C2 domain of CatSperτ.
  2. This presumably impairs CatSperτ function or stability. This is not demonstrated for H113R.
  3. In mouse, CatSperτ is a membrane-associating C2-domain protein that reaches the flagellum on its own. It targets the CatSper channel into the quadrilinear Ca²⁺-signaling nanodomains of the sperm flagellar membrane. It is not needed for the channel to assemble (Hwang et al., Cell Rep 2022, PMID 34998468).
  4. Without CatSperτ, the knockout sperm form a functional CatSper channel only at significantly reduced levels. The sperm conduct Ca²⁺ but fail to hyperactivate (bioRxiv). A separate preprint reports C2CD6 as essential for CatSper complex assembly (Yang et al., bioRxiv). The two groups differ on whether the channel assembles.
  5. Failed hyperactivation leads to failed fertilization in vitro and in vivo, so the male is infertile.
  6. The mouse knockouts have no reported acrosome defect, but the human patient has globozoospermia. This is an unresolved mismatch.

Terms to consider (verify before binding): - GO: sperm flagellum, cation channel complex, sperm hyperactivation, calcium ion transmembrane transport. - CL: spermatozoon, spermatid. - UBERON: testis, sperm flagellum principal piece. - CatSper is a principal piece protein complex.

Immune, metabolic and omics findings: none reported.

7. Anatomical structures affected

  • Organ: testis (spermatogenesis and sperm morphology).
  • Cells: spermatids and spermatozoa.
  • Subcellular: acrosome, sperm head and flagellar membrane.
  • Lateralization: not applicable.
  • Other organs: none. No syndromic features are reported.

8. Temporal development

The disease is congenital as a genetic condition but is detected in adulthood, through male factor infertility. It is stable and lifelong. No remission is reported.

9. Inheritance and population

  • Inheritance: autosomal recessive. The one patient was homozygous.
  • Population: one Moroccan man. Consanguinity, founder effect, penetrance, expressivity, prevalence and carrier frequency are not reported.
  • Sex and age: male only. Adults.

10. Diagnostics

  • Semen analysis: normal sperm count with globozoospermia. Acrosomeless sperm can be confirmed by Papanicolaou staining or acrosome-marker staining, and by electron microscopy.
  • Genetic testing: exome sequencing or a globozoospermia or male-infertility gene panel. Panel inclusion of CATSPERT varies, so check with the laboratory.
  • Differential diagnosis: DPY19L2-related globozoospermia is the main genetic cause. Others include GGN and further candidate genes (Celse et al., Hum Genet 2021, PMID 33108537). Also exclude other CatSper-gene disorders.
  • Functional tests: CatSper function can be assessed in patient sperm. One preprint argues that defective CatSper function is a frequent cause of unexplained infertility (medRxiv 2023), but it is not peer-reviewed.

11. Prognosis

Natural fertility is unlikely. Other health is not reported to be affected. Prognosis for conception depends on assisted reproduction, below.

12. Treatment

No treatment is specific to SPGF68. No clinical trials are known to me.

  • Standard care for globozoospermia: intracytoplasmic sperm injection (ICSI), sometimes with assisted oocyte activation. For this gene there is no outcome data. For globozoospermia in general, ICSI results are often poor because of fertilization failure. Check the systematic review (Crafa et al., World J Mens Health 2023, PMID 36047070) before citing.
  • Mouse rescue: OMIM's gene entry says sterility was transiently rescued with a calcium ionophore, starvation, or both. I did not verify this directly.
  • Counseling: genetic counseling.
  • NCIT terms: look up the terms for intracytoplasmic sperm injection and genetic counseling. The CLAUDE.md lists NCIT:C15240 for genetic counseling.

13. Prevention

  • Prevention levels: primary and secondary prevention do not apply, since the disease is recessive and congenital.
  • Screening: carrier screening is not established.
  • Reproductive options: genetic counseling and family testing if the variant is known.

14. Other species and natural disease

No natural disease is documented. The mouse ortholog is Catspert (MGI:1920713 per search results; verify), with NCBI Taxon 10090 for mouse. OMIA coverage was not checked.

15. Model organisms

  • Mouse knockouts: male C2cd6/Catspert knockout mice are sterile. They show defective hyperactivation and fail fertilization in vitro and in vivo. OMIM attributes this to two groups, Yang et al. and Hwang et al. (Cell Rep 2022, PMID 34998468; Yang et al. bioRxiv). I did not find a published journal version of the Yang paper.
  • Evidence type: MODEL_ORGANISM.
  • Fidelity: male infertility is reproduced. Globozoospermia (the human hallmark) was not described in the mouse results I saw. Suggest a HUMAN_MODEL_MISMATCH discussion, with PARTIALLY_RECAPITULATES.
  • Related CatSper knockouts: Catsper1, Catsper2, Catsper3 and Catsper4 knockouts also cause infertility with impaired hyperactivation (PubMed 14657366; Biol Reprod 2007). Reviews: Hwang & Chung, Physiology 2023, PMID 36512352.

Gaps to resolve before curating

  1. Fetch Oud et al. 2020, find its PMID, and quote the CATSPERT/C2CD6 patient description (genotype, semen findings, ICSI history).
  2. Confirm the gene symbol and HGNC ID, and check whether OMIM #619805 now cites more patients.
  3. Resolve why a human acrosome defect appears with a mouse hyperactivation defect, and look for any functional data on H113R.
  4. Check the GeneReviews and ClinGen baselines. I did not search either, and I did not find a GeneReviews chapter.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 4
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 6
Resolved 4
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 2
Terms named correctly 1
Terms named as a different term 1

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:

  • HP:0034307 (1 mention) - the report calls it "Globozoospermia"; HP calls it Elevated left ventricular end-diastolic diameter

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, MGI.