Spermatogenic Failure 51

Mendelian MONDO:0030926 Pathograph 11 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 51 (SPGF51) is autosomal recessive male infertility caused by biallelic variants in CFAP91 (formerly MAATS1 or AAT1). CFAP91 is a subunit of the calmodulin- and spoke-associated complex (CSC), which with CFAP61 and CFAP251 builds the base of radial spoke 3 (RS3); CFAP91 also extends along the doublet microtubule to the base of radial spoke 2 and acts as the scaffold on which RS3 is assembled. Loss of CFAP91 prevents CFAP251 and other RS3 proteins from being incorporated into the sperm flagellum. Affected men have severe astheno-teratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF), and electron microscopy shows central pair complex and radial spoke defects. The disease is known from six unrelated men identified by exome sequencing of an MMAF cohort, with supporting data from Trypanosoma and Tetrahymena orthologue knockdowns and a Cfap91 knockout mouse with immotile, short-tailed sperm. Respiratory involvement has not been reported in patients. ICSI is the usual route to fertility for MMAF, but CFAP91-specific outcome data are limited.

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Inheritance

1
Autosomal recessive HP:0000007
All reported patients are homozygous for deleterious CFAP91 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein."
Homozygous variants in six unrelated men.
◈

Mechanistic Hypotheses

1
CFAP91 loss affects sperm flagella but spares other motile cilia
cfap91_motile_cilia_involvement EMERGING
Evidence balance 1 support 2 refute
CFAP91 is part of the RS3 base in respiratory and ependymal cilia as well as sperm. No respiratory phenotype has been reported in patients, but the human report could only be read as an abstract, so absence was not confirmed. In Cfap91 knockout mice, tracheal and ependymal cilia grow normally on a mixed background, whereas on the B6D2 background knockouts were under-represented and died before 8 weeks, which the authors attributed, without confirming it, to hydrocephalus. In Tetrahymena, CFAP91 loss severely disrupts ciliary beating. Whether CFAP91 loss affects human motile cilia is therefore unresolved.
Show evidence (3 references)
PMID:40931011 SUPPORT Model organism
"However, there were no apparent differences found between Cfap91+/- and Cfap91-/- mice (Supplementary Fig. 3e), indicating that ciliary elongation was endurable in Cfap91-/- mice in contrast to disrupted sperm flagellum formation."
Tracheal and ependymal cilia are of normal length in knockout mice.
PMID:40931011 REFUTE Model organism
"As mutations in other Cfap genes were reported to cause hydrocephalus37,38, we hypothesized that Cfap91-/- mice in the B6D2 background may also carry hydrocephalus."
Early death of knockouts on one background suggests a role outside sperm, though hydrocephalus was hypothesized rather than shown.
PMID:36552811 REFUTE Model organism
"Cilia of Tetrahymena cells with knocked-out CFAP91 beat in an uncoordinated manner and their beating frequency is dramatically reduced."
In a ciliate, CFAP91 is needed for ciliary motility.
⚙

Pathophysiology

4
Loss of CFAP91
Biallelic deleterious CFAP91 variants. CFAP91 is a structural scaffold of the axonemal doublet: its N-terminal region runs from the base of RS2 to the base of RS3, and its C-terminal region extends up the RS3 neck. It binds CFAP251 before flagellar outgrowth and later recruits LRRC23 to the spoke.
CFAP91 hgnc:24010 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP91 (hgnc:24010). hgnc:24010 is a gene from the HUGO Gene Nomenclature Committee.
structural constituent of the axonemal cytoskeleton GO:0005200 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased structural constituent of the axonemal cytoskeleton, annotated with structural constituent of cytoskeleton (GO:0005200). GO:0005200 is a molecular function from the Gene Ontology.
Radial spoke base 3 GO:0120342 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Radial spoke base 3 (GO:0120342). GO:0120342 is a cellular component from the Gene Ontology.
Downstream
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme Without CFAP91, CFAP251 and LRRC23 are present in testis but fail to incorporate into the sperm flagellum.
Show evidence (3 references)
PMID:40931011 SUPPORT Model organism
"Using a transgenic rescue model expressing FLAG- and BioID2-tagged CFAP91, we reveal that CFAP91 immunoprecipitates with RS3 proteins CFAP251 and LRRC23, whose localization is disrupted in Cfap91 KO sperm flagella."
CFAP91 binds RS3 proteins in mouse testis.
PMID:40931011 SUPPORT BACKGROUND In vitro / ex vivo
"Notably, according to a high-resolution study published recently, CFAP91 has been shown to exhibit a distinctive localization in bovine sperm axoneme: the N-terminal region of CFAP91 is localized from the RS2 base to the RS3 base through the base plate of the nexin-dynein regulatory complex..."
Structural position of CFAP91 in the bovine sperm axoneme, summarised from a cited cryo-EM study.
PMID:17967944 SUPPORT Model organism
"FAP91 directly interacts with radial spoke protein 3 (an AKAP), which is located at the base of the spoke."
In Chlamydomonas the CFAP91 orthologue is a CaM-associated protein bound to the radial spoke base.
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
The CSC (CFAP61, CFAP91 and CFAP251 with calmodulin) sits at the base of radial spoke 3 and links it to the doublet microtubules. Loss of any one subunit destabilizes the others. Without CFAP91, CFAP251 and LRRC23 are not incorporated into the sperm flagellum, CFAP251 is reduced in patient sperm, and in Tetrahymena the RS3 base and the base of RS2 are not stably docked.
Radial spoke assembly GO:0062177 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Radial spoke assembly (GO:0062177). GO:0062177 is a biological process from the Gene Ontology.
Radial spoke 3 GO:0120335 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Radial spoke 3 (GO:0120335). GO:0120335 is a cellular component from the Gene Ontology.
Animal models
Cfap91 knockout mouse Mouse recapitulates CFAP251 and LRRC23 are not incorporated into knockout sperm flagella.
Downstream
Sperm Axonemal Disorganization Radial spokes anchor the central pair and connect it to the dynein arms; without RS3 and a stable RS2 base the central pair is lost and the axoneme becomes disordered. How loss of these spoke bases leads to failure of the whole sperm flagellum is not established.
Show evidence (3 references)
PMID:32161152 SUPPORT Human clinical
"Moreover, we confirmed that the WDR66 protein is a physical and functional partner of CFAP91 into the CSC."
CFAP91 and CFAP251 (WDR66) are partners in the human sperm CSC.
PMID:40931011 SUPPORT BACKGROUND Human clinical
"CFAP251 was downregulated in the spermatozoa of human patients carrying a pathogenic variant in CFAP9126."
Reduced CFAP251 in sperm of CFAP91 patients, as summarised from the primary report.
PMID:36552811 SUPPORT Model organism
"The localization studies confirmed that the level of RS3-specific proteins, Cfap61 and Cfap251, as well as RS2-associated Cfap206, are significantly diminished in Tetrahymena CFAP91-KO cells."
In Tetrahymena, CFAP91 knockout depletes the other CSC subunits and an RS2 base protein.
Sperm Axonemal Disorganization
Patient sperm show severe central pair complex and radial spoke defects, with partial loss of the central pair protein SPAG6 and the radial spoke protein RSPH1. In knockout mice the axoneme is disordered from the spermatid stage, with mitochondrial sheath, outer dense fiber and fibrous sheath abnormalities.
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.
Axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology. Axonemal central apparatus GO:1990716 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axonemal central apparatus (GO:1990716). GO:1990716 is a cellular component from the Gene Ontology.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Abnormal sperm axoneme morphology
Show evidence (3 references)
PMID:32161152 SUPPORT Human clinical
"TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects."
Central pair and radial spoke defects in patient sperm.
PMID:35174165 SUPPORT BACKGROUND Human clinical
"Though the localization pattern of CFAP91 was yet uncharacterized, MMAF patients carrying CFAP91 variants displayed defects in ultrastructure of sperm flagella including absence of CP, and IF staining also showed partially loss of CP protein SPAG6 and RS protein RSPH1"
A later paper's summary of the CFAP91 patient ultrastructure and immunostaining.
PMID:40931011 SUPPORT Model organism
"In addition, abnormalities were found in the mitochondrial sheath, outer dense fiber, and fibrous sheath in Cfap91 KO spermatozoa (Fig. 3d–h)."
Peri-axonemal disorganization in knockout mice.
Multiple Morphological Abnormalities of the Sperm Flagella
Severe astheno-teratozoospermia with malformed flagella (MMAF); motility is severely reduced or absent.
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 assembly GO:0120316 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm flagellum assembly (GO:0120316). GO:0120316 is a biological process from the Gene Ontology.
Animal models
Cfap91 knockout mouse Mouse partially recapitulates Short-tailed immotile sperm, with a more severe count reduction than is documented in patients.
Downstream
Reduced sperm motility
Abnormal sperm morphology
Male infertility Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
Show evidence (2 references)
PMID:32161152 SUPPORT Human clinical
"We showed that CFAP91 is essential for normal sperm flagellum structure and function in human and Trypanosoma and that biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility."
Flagellar malformation is the human phenotype.
PMID:40931011 SUPPORT Model organism
"Here, we demonstrate that Cfap91 knockout (KO) mice exhibit impaired sperm flagellum formation and male infertility."
Flagellum formation fails in knockout mice.
⬡

Pathograph

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Pathograph: causal mechanism network for Spermatogenic Failure 51 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
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 (1 reference)
PMID:32161152 SUPPORT Human clinical
"biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
Primary male infertility in patients.
Reduced sperm motility Reproductive HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
The study concludes that biallelic CFAP91 variants cause astheno-teratozoospermia, which includes reduced motility.
Abnormal sperm morphology Reproductive HP:0012864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Teratozoospermia, annotated with Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
The study concludes that biallelic CFAP91 variants cause severe flagellar malformations and astheno-teratozoospermia.
Abnormal sperm axoneme morphology Reproductive HP:0033524 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm axoneme morphology (HP:0033524). HP:0033524 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects."
Axonemal ultrastructure defects in patient sperm.
🧬

Genetic Associations

1
CFAP91 (Causal)
Gene: CFAP91 hgnc:24010 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP91 (hgnc:24010). hgnc:24010 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:32161152 SUPPORT Human clinical
"We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein."
Primary gene-disease report.
PMID:34529793 SUPPORT Human clinical
"identified homozygous or compound heterozygous pathogenic mutations in CFAP43, CFAP44, CFAP69, DNAH1, DNAH8, AK7, TTC29 and MAATS1 in 13 patients"
MAATS1 among the causal genes in an independent French MMAF series.
💊

Medical Actions

2
Intracytoplasmic Sperm Injection
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
ICSI bypasses the motility defect and is the standard fertility treatment for MMAF. In a French series of 20 MMAF couples, which included the genetic causes found in the cohort (MAATS1 among them), fertilization rates after ICSI matched those of non-MMAF couples and did not differ by genotype. Outcome data for CFAP91 carriers specifically are not available.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion and form irrelevant to fertilization.
Show evidence (1 reference)
PMID:34529793 SUPPORT INDIRECT Human clinical
"Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect."
Applies to MMAF across genotypes; not reported separately for CFAP91.
Show evidence (1 reference)
PMID:34529793 SUPPORT INDIRECT Human clinical
"The fertilisation rate was not statistically different between the MMAF (65.7%) and the non-MMAF (66.0%) couples and it did not differ according to the genotype or the flagellar phenotype of the subjects or use of the HOS test."
Group-level MMAF outcome data from a series that included CFAP91; the CFAP91 couple's own result is not reported in the abstract.
Genetic Counseling
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
Platform: Behavioral / lifestyle
Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP91 variants are known; sons conceived by ICSI inherit one variant.
Show evidence (1 reference)
PMID:34529793 SUPPORT INDIRECT Human clinical
"An early and extensive phenotypic and genetic investigation should be considered for all men requiring ICSI for severe asthenozoospermia."
Recommendation for genetic work-up of MMAF before ICSI, which underpins counselling.
🔬

Diagnosis

3
Molecular Genetic Testing
Establishes the diagnosis; patients were identified by exome sequencing of an MMAF cohort.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"Exome sequencing was performed on 167 infertile men with an MMAF phenotype."
Exome sequencing identified the patients.
Semen Analysis
Shows reduced progressive motility with an excess of absent, short, coiled or irregular flagella, the MMAF pattern that prompts genetic testing.
Show evidence (1 reference)
PMID:34529793 SUPPORT Human clinical
"Patients with MMAF were recruited based on reduced sperm progressive motility and increased frequencies of absent, short, coiled or irregular flagella compared with those in sperm from fertile control men."
Semen analysis criteria for MMAF in a series that included a CFAP91 patient.
Transmission Electron Microscopy of Sperm Flagella
Shows central pair complex and radial spoke defects.
Transmission Electron Microscopy NCIT:C18216 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32161152 SUPPORT Human clinical
"Immunostaining and transmission electron microscopy (TEM) in sperm cells from affected individuals were performed to characterise the ultrastructural sperm defects."
TEM and immunostaining were used to characterise patient sperm.
🐁

Animal Models

1
Cfap91 knockout mouse
Knockout males are infertile with oligo-astheno-teratozoospermia: few, completely immotile sperm with short tails and abnormal heads, disordered axonemes and peri-axonemal defects. CFAP251 and LRRC23 fail to enter the flagellum. On the B6D2 background knockouts were under-represented and all died before 8 weeks of age.
Species
Mouse
Genotype
Cfap91-/- (32-kb deletion), homozygous, B6D2/129 background
Publication
PMID:40931011
Pathograph links
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme recapitulates fidelity: high observes: molecular CFAP251 and LRRC23 are not incorporated into knockout sperm flagella.
Show evidence (1 reference)
PMID:40931011 SUPPORT Model organism
"Overall, these data suggested that the localization of CFAP91-associating RS3 proteins was disrupted in sperm tails of Cfap91-/- males."
RS3 proteins mislocalize without CFAP91.
Multiple Morphological Abnormalities of the Sperm Flagella partially recapitulates fidelity: moderate observes: cellular Short-tailed immotile sperm, with a more severe count reduction than is documented in patients.
Limitations: Knockout males have very few epididymal sperm, and the strain-dependent early death has no counterpart in reported patients.
Divergences from the human mechanism
species mismatch qualifying
Mouse knockouts have oligozoospermia with few sperm reaching the cauda epididymis, whereas the human phenotype is reported as astheno-teratozoospermia; whether patients also have low counts is not stated in the available human source.
other immaterial
On the B6D2 inbred background Cfap91 knockouts died before 8 weeks of age, possibly from hydrocephalus, while on a mixed B6D2/129 background they survived. The lethality is a mouse strain effect and does not bear on the sperm phenotype studied in survivors.
Show evidence (2 references)
PMID:40931011 SUPPORT Model organism
"Furthermore, spermatozoa from Cfap91-/- cauda epididymis showed abnormal morphology (Fig. 2a), including shorter tails (Fig. 2b) and abnormal heads (Fig. 2c)."
Short-tailed, malformed sperm in knockout mice.
+ 1 more reference
{ }

Source YAML

click to show 
name: Spermatogenic Failure 51
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF51
- spermatogenic failure 51
- CFAP91-related multiple morphological abnormalities of the sperm flagella
- MAATS1-related astheno-teratozoospermia
description: >-
  Spermatogenic failure 51 (SPGF51) is autosomal recessive male infertility
  caused by biallelic variants in CFAP91 (formerly MAATS1 or AAT1). CFAP91 is a
  subunit of the calmodulin- and spoke-associated complex (CSC), which with
  CFAP61 and CFAP251 builds the base of radial spoke 3 (RS3); CFAP91 also
  extends along the doublet microtubule to the base of radial spoke 2 and acts
  as the scaffold on which RS3 is assembled. Loss of CFAP91 prevents CFAP251
  and other RS3 proteins from being incorporated into the sperm flagellum.
  Affected men have severe astheno-teratozoospermia with multiple
  morphological abnormalities of the sperm flagella (MMAF), and electron
  microscopy shows central pair complex and radial spoke defects.

  The disease is known from six unrelated men identified by exome sequencing
  of an MMAF cohort, with supporting data from Trypanosoma and Tetrahymena
  orthologue knockdowns and a Cfap91 knockout mouse with immotile,
  short-tailed sperm. Respiratory involvement has not been reported in
  patients. ICSI is the usual route to fertility for MMAF, but
  CFAP91-specific outcome data are limited.
disease_term:
  preferred_term: spermatogenic failure 51
  term:
    id: MONDO:0030926
    label: spermatogenic failure 51
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 619177. ClinGen has not
  classified CFAP91 for spermatogenic failure 51: no CFAP91 row is present in
  the ClinGen gene-disease validity export dated 2026-10-14
  (data/clingen/gene_validity.csv), so gene_disease_validity is left absent.
  The only cached text of the primary human report (PMID:32161152) is its
  abstract, so the number of patients with each phenotype, the variant list,
  sperm counts and the patients' respiratory history could not be quoted; the
  abstract gives six unrelated homozygous men. A CFAP91 carrier was among the
  MMAF patients of a French ICSI series (PMID:34529793), but the cached
  abstract does not report that couple's outcome separately. No GeneReviews
  chapter covers this disease (Bookshelf index snapshot 2026-09-10).
inheritance:
- name: Autosomal recessive
  description: >-
    All reported patients are homozygous for deleterious CFAP91 variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein."
    explanation: Homozygous variants in six unrelated men.
pathophysiology:
- name: Loss of CFAP91
  description: >-
    Biallelic deleterious CFAP91 variants. CFAP91 is a structural scaffold of
    the axonemal doublet: its N-terminal region runs from the base of RS2 to
    the base of RS3, and its C-terminal region extends up the RS3 neck. It
    binds CFAP251 before flagellar outgrowth and later recruits LRRC23 to the
    spoke.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP91
    term:
      id: hgnc:24010
      label: CFAP91
  molecular_functions:
  - preferred_term: structural constituent of the axonemal cytoskeleton
    modifier: DECREASED
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  cellular_components:
  - preferred_term: Radial spoke base 3
    term:
      id: GO:0120342
      label: radial spoke base 3
  downstream:
  - target: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
    causal_link_type: DIRECT
    description: >-
      Without CFAP91, CFAP251 and LRRC23 are present in testis but fail to
      incorporate into the sperm flagellum.
    evidence:
    - reference: PMID:40931011
      reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hence, depletion of CFAP91 disabled the incorporation of CFAP251 into the sperm flagella"
      explanation: CFAP91 is needed to bring CFAP251 into the flagellum.
  evidence:
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using a transgenic rescue model expressing FLAG- and BioID2-tagged CFAP91, we reveal that CFAP91 immunoprecipitates with RS3 proteins CFAP251 and LRRC23, whose localization is disrupted in Cfap91 KO sperm flagella."
    explanation: CFAP91 binds RS3 proteins in mouse testis.
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "Notably, according to a high-resolution study published recently, CFAP91 has been shown to exhibit a distinctive localization in bovine sperm axoneme: the N-terminal region of CFAP91 is localized from the RS2 base to the RS3 base through the base plate of the nexin-dynein regulatory complex (N-DRC) and is intertwined with the protofilament formed by CCDC39/4033,34."
    explanation: Structural position of CFAP91 in the bovine sperm axoneme, summarised from a cited cryo-EM study.
  - reference: PMID:17967944
    reference_title: "A conserved CaM- and radial spoke associated complex mediates regulation of flagellar dynein activity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FAP91 directly interacts with radial spoke protein 3 (an AKAP), which is located at the base of the spoke."
    explanation: In Chlamydomonas the CFAP91 orthologue is a CaM-associated protein bound to the radial spoke base.
- name: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
  description: >-
    The CSC (CFAP61, CFAP91 and CFAP251 with calmodulin) sits at the base of
    radial spoke 3 and links it to the doublet microtubules. Loss of any one
    subunit destabilizes the others. Without CFAP91, CFAP251 and LRRC23 are not
    incorporated into the sperm flagellum, CFAP251 is reduced in patient sperm,
    and in Tetrahymena the RS3 base and the base of RS2 are not stably docked.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Radial spoke 3
    term:
      id: GO:0120335
      label: radial spoke 3
  biological_processes:
  - preferred_term: Radial spoke assembly
    modifier: DECREASED
    term:
      id: GO:0062177
      label: radial spoke assembly
  downstream:
  - target: Sperm Axonemal Disorganization
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Radial spokes anchor the central pair and connect it to the dynein arms;
      without RS3 and a stable RS2 base the central pair is lost and the
      axoneme becomes disordered. How loss of these spoke bases leads to
      failure of the whole sperm flagellum is not established.
    evidence:
    - reference: PMID:32161152
      reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Knockdown of TbCFAP91 using RNAi impaired flagellar movement led to CPC defects in Trypanosoma as observed in humans."
      explanation: Knockdown of the Trypanosoma orthologue reproduces the central pair defect.
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, we confirmed that the WDR66 protein is a physical and functional partner of CFAP91 into the CSC."
    explanation: CFAP91 and CFAP251 (WDR66) are partners in the human sperm CSC.
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "CFAP251 was downregulated in the spermatozoa of human patients carrying a pathogenic variant in CFAP9126."
    explanation: Reduced CFAP251 in sperm of CFAP91 patients, as summarised from the primary report.
  - reference: PMID:36552811
    reference_title: "Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The localization studies confirmed that the level of RS3-specific proteins, Cfap61 and Cfap251, as well as RS2-associated Cfap206, are significantly diminished in Tetrahymena CFAP91-KO cells."
    explanation: In Tetrahymena, CFAP91 knockout depletes the other CSC subunits and an RS2 base protein.
- name: Sperm Axonemal Disorganization
  description: >-
    Patient sperm show severe central pair complex and radial spoke defects,
    with partial loss of the central pair protein SPAG6 and the radial spoke
    protein RSPH1. In knockout mice the axoneme is disordered from the
    spermatid stage, with mitochondrial sheath, outer dense fiber and fibrous
    sheath abnormalities.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects."
    explanation: Central pair and radial spoke defects in patient sperm.
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Though the localization pattern of CFAP91 was yet uncharacterized, MMAF patients carrying CFAP91 variants displayed defects in ultrastructure of sperm flagella including absence of CP, and IF staining also showed partially loss of CP protein SPAG6 and RS protein RSPH1"
    explanation: A later paper's summary of the CFAP91 patient ultrastructure and immunostaining.
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, abnormalities were found in the mitochondrial sheath, outer dense fiber, and fibrous sheath in Cfap91 KO spermatozoa (Fig. 3d–h)."
    explanation: Peri-axonemal disorganization in knockout mice.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    Severe astheno-teratozoospermia with malformed flagella (MMAF); motility is
    severely reduced or absent.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Abnormal sperm morphology
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We showed that CFAP91 is essential for normal sperm flagellum structure and function in human and Trypanosoma and that biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility."
    explanation: Flagellar malformation is the human phenotype.
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we demonstrate that Cfap91 knockout (KO) mice exhibit impaired sperm flagellum formation and male infertility."
    explanation: Flagellum formation fails in knockout mice.
mechanistic_hypotheses:
- hypothesis_group_id: cfap91_motile_cilia_involvement
  hypothesis_label: CFAP91 loss affects sperm flagella but spares other motile cilia
  status: EMERGING
  description: >-
    CFAP91 is part of the RS3 base in respiratory and ependymal cilia as well
    as sperm. No respiratory phenotype has been reported in patients, but the
    human report could only be read as an abstract, so absence was not
    confirmed. In Cfap91 knockout mice, tracheal and ependymal cilia grow
    normally on a mixed background, whereas on the B6D2 background knockouts
    were under-represented and died before 8 weeks, which the authors
    attributed, without confirming it, to hydrocephalus. In Tetrahymena,
    CFAP91 loss severely disrupts ciliary beating. Whether CFAP91 loss affects
    human motile cilia is therefore unresolved.
  evidence:
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, there were no apparent differences found between Cfap91+/- and Cfap91-/- mice (Supplementary Fig. 3e), indicating that ciliary elongation was endurable in Cfap91-/- mice in contrast to disrupted sperm flagellum formation."
    explanation: Tracheal and ependymal cilia are of normal length in knockout mice.
  - reference: PMID:40931011
    reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "As mutations in other Cfap genes were reported to cause hydrocephalus37,38, we hypothesized that Cfap91-/- mice in the B6D2 background may also carry hydrocephalus."
    explanation: >-
      Early death of knockouts on one background suggests a role outside
      sperm, though hydrocephalus was hypothesized rather than shown.
  - reference: PMID:36552811
    reference_title: "Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Cilia of Tetrahymena cells with knocked-out CFAP91 beat in an uncoordinated manner and their beating frequency is dramatically reduced."
    explanation: In a ciliate, CFAP91 is needed for ciliary motility.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
    explanation: Primary male infertility in patients.
- category: Reproductive
  name: Reduced sperm motility
  description: Severe asthenozoospermia, part of the astheno-teratozoospermia reported in all patients.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
    explanation: The study concludes that biallelic CFAP91 variants cause astheno-teratozoospermia, which includes reduced motility.
- category: Reproductive
  name: Abnormal sperm morphology
  description: >-
    Teratozoospermia with multiple morphological abnormalities of the flagella.
    The cached sources do not give the proportions of absent, short, coiled or
    irregular flagella in CFAP91 patients, so the individual flagellar
    phenotypes are not recorded separately.
  phenotype_term:
    preferred_term: Teratozoospermia
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility"
    explanation: The study concludes that biallelic CFAP91 variants cause severe flagellar malformations and astheno-teratozoospermia.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: Severe central pair complex and radial spoke defects on electron microscopy.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects."
    explanation: Axonemal ultrastructure defects in patient sperm.
genetic:
- name: CFAP91
  association: Causal
  gene_term:
    preferred_term: CFAP91
    term:
      id: hgnc:24010
      label: CFAP91
  notes: >-
    Six unrelated homozygous men from an exome study of 167 MMAF patients; the
    individual variants are not given in the cached abstract. ClinGen has not
    classified this gene-disease pair.
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein."
    explanation: Primary gene-disease report.
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified homozygous or compound heterozygous pathogenic mutations in CFAP43, CFAP44, CFAP69, DNAH1, DNAH8, AK7, TTC29 and MAATS1 in 13 patients"
    explanation: MAATS1 among the causal genes in an independent French MMAF series.
animal_models:
- name: Cfap91 knockout mouse
  species: Mouse
  genotype: Cfap91-/- (32-kb deletion), homozygous, B6D2/129 background
  publication: PMID:40931011
  description: >-
    Knockout males are infertile with oligo-astheno-teratozoospermia: few,
    completely immotile sperm with short tails and abnormal heads, disordered
    axonemes and peri-axonemal defects. CFAP251 and LRRC23 fail to enter the
    flagellum. On the B6D2 background knockouts were under-represented and all
    died before 8 weeks of age.
  modeled_mechanisms:
  - target: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: CFAP251 and LRRC23 are not incorporated into knockout sperm flagella.
    evidence:
    - reference: PMID:40931011
      reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, these data suggested that the localization of CFAP91-associating RS3 proteins was disrupted in sperm tails of Cfap91-/- males."
      explanation: RS3 proteins mislocalize without CFAP91.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Short-tailed immotile sperm, with a more severe count reduction than is documented in patients.
    limitations: >-
      Knockout males have very few epididymal sperm, and the strain-dependent
      early death has no counterpart in reported patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse knockouts have oligozoospermia with few sperm reaching the cauda
        epididymis, whereas the human phenotype is reported as
        astheno-teratozoospermia; whether patients also have low counts is not
        stated in the available human source.
    - divergence_type: OTHER
      materiality: IMMATERIAL
      description: >-
        On the B6D2 inbred background Cfap91 knockouts died before 8 weeks of
        age, possibly from hydrocephalus, while on a mixed B6D2/129 background
        they survived. The lethality is a mouse strain effect and does not bear
        on the sperm phenotype studied in survivors.
    evidence:
    - reference: PMID:40931011
      reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, spermatozoa from Cfap91-/- cauda epididymis showed abnormal morphology (Fig. 2a), including shorter tails (Fig. 2b) and abnormal heads (Fig. 2c)."
      explanation: Short-tailed, malformed sperm in knockout mice.
    - reference: PMID:40931011
      reference_title: "Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistently, fewer number of spermatozoa were found in the cauda epididymis of Cfap91-/- males (Supplementary Fig. 3d)."
      explanation: Records the low sperm count behind the species divergence.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect and is the standard fertility treatment
    for MMAF. In a French series of 20 MMAF couples, which included the
    genetic causes found in the cohort (MAATS1 among them), fertilization rates
    after ICSI matched those of non-MMAF couples and did not differ by
    genotype. Outcome data for CFAP91 carriers specifically are not available.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection makes flagellar propulsion and form irrelevant to fertilization.
    evidence:
    - reference: PMID:34529793
      reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect."
      explanation: Applies to MMAF across genotypes; not reported separately for CFAP91.
  evidence:
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The fertilisation rate was not statistically different between the MMAF (65.7%) and the non-MMAF (66.0%) couples and it did not differ according to the genotype or the flagellar phenotype of the subjects or use of the HOS test."
    explanation: Group-level MMAF outcome data from a series that included CFAP91; the CFAP91 couple's own result is not reported in the abstract.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP91 variants are known; sons conceived by
    ICSI inherit one variant.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "An early and extensive phenotypic and genetic investigation should be considered for all men requiring ICSI for severe asthenozoospermia."
    explanation: Recommendation for genetic work-up of MMAF before ICSI, which underpins counselling.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis; patients were identified by exome sequencing of
    an MMAF cohort.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing was performed on 167 infertile men with an MMAF phenotype."
    explanation: Exome sequencing identified the patients.
- name: Semen Analysis
  description: >-
    Shows reduced progressive motility with an excess of absent, short, coiled
    or irregular flagella, the MMAF pattern that prompts genetic testing.
  evidence:
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with MMAF were recruited based on reduced sperm progressive motility and increased frequencies of absent, short, coiled or irregular flagella compared with those in sperm from fertile control men."
    explanation: Semen analysis criteria for MMAF in a series that included a CFAP91 patient.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: Shows central pair complex and radial spoke defects.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:32161152
    reference_title: "Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunostaining and transmission electron microscopy (TEM) in sperm cells from affected individuals were performed to characterise the ultrastructural sperm defects."
    explanation: TEM and immunostaining were used to characterise patient sperm.
📚

References & Deep Research

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Evaluations and curation notes (1)

Create: Spermatogenic_Failure_51 · 2026-10-16T13:41:26Z · View source

Created the SPGF51 entry for CFAP91 (MAATS1)-related male infertility (MONDO:0030926). Sources: a claude_code deep-research report (research/Spermatogenic_Failure_51-deep-research-claude_code.md, preflight PASS) used as leads only, plus PubMed searches. Human evidence is thin: the primary report (Martinez 2020, six homozygous men) is cached as abstract only, and a French ICSI series (2021) lists MAATS1 among its causes without per-genotype outcomes, so ICSI evidence is marked directness INDIRECT. Mechanistic evidence comes from the Cfap91 knockout mouse with BioID2 proximity labelling (Wang 2025, refetched as full text), Tetrahymena Cfap91 knockout (2022) and the Chlamydomonas CSC paper (Dymek and Smith 2007). Pathograph mirrors SPGF33/SPGF84: Loss of CFAP91 (GO:0005200 DECREASED) -> loss of the CSC -> sperm axonemal disorganization -> MMAF -> phenotypes. Individual flagellar shape phenotypes are not recorded because no gene-specific human quote was available; teratozoospermia is bound to HP:0012864. An EMERGING hypothesis records that motile-cilia involvement is unresolved (normal mouse airway cilia vs strain-dependent early death and Tetrahymena beat defects). Mouse model carries SPECIES_MISMATCH and OTHER divergences. ClinGen has not classified the pair and there is no GeneReviews chapter. All validation recipes passed, including validate-disorders. Stub deleted.

Claude Code ▸
Research Report: Spermatogenic Failure 51 (SPGF51; CFAP91/MAATS1-related MMAF)
claude-haiku-5-5, claude-sonnet-5-5 5 citations 2026-10-16T13:13:12.837504

Research Report: Spermatogenic Failure 51 (SPGF51; CFAP91/MAATS1-related MMAF)

Evidence base. I could check only a few sources: search snippets, the Disease Ontology entry as reported by a search, and MalaCards. The OMIM page returned 403 and the JMG full text returned 429. The report rests on one primary human study, one mouse knockout paper, and one Tetrahymena paper. Items marked [unverified] come from my background knowledge or from a search summary that I did not confirm against the source. I have no exact abstract quotes to offer. Before they are used as evidence snippets, quotes must be pulled with just fetch-reference.

1. Disease information

  • Overview: SPGF51 is an autosomal recessive form of male infertility. It is a severe asthenoteratozoospermia of the "multiple morphological abnormalities of the sperm flagella" (MMAF) type. Flagellar defects reduce or abolish sperm motility. The causal gene is CFAP91 (alias MAATS1) at 3q13.33.
  • Identifiers:
  • OMIM #619177, per an MGI listing returned by search. I did not confirm it on OMIM.
  • Disease Ontology DOID:0112273, with parents DOID:0050737 and DOID:0111910.
  • MONDO:0030926, as given in the template. A search suggested this is SPGF51, but the mapping was not confirmed. Check it in the MONDO browser.
  • Orphanet, ICD and MeSH identifiers were not retrieved. MalaCards lists a "Spermatogenic Failure 51 (SPGF51)" card.
  • Synonyms: SPGF51; CFAP91-related asthenoteratozoospermia; MAATS1-related MMAF.
  • Data origin: Disease-level, from research exome cohorts and OMIM/DO curation. It is not derived from EHR data.

2. Etiology

  • Cause: Biallelic (homozygous or compound heterozygous) loss-of-function variants in CFAP91.
  • Genetic risk factors: None known beyond the causal gene.
  • Environmental risk factors, protective factors and gene-environment interactions: None documented in the sources I found.

3. Phenotypes

All data are from Martinez et al. 2020, J Med Genet 57(10):708 (PMID:32161152, per a bvsalud record). The study identified six unrelated men from a cohort of 167 MMAF cases.

Phenotype Suggested HPO term Notes
Male infertility HP:0003251 All patients.
Asthenozoospermia HP:0012206 Severely reduced to absent motility.
Teratozoospermia HP:0012864 Absent, short, bent, coiled and irregular-caliber tails.
Abnormal sperm flagella morphology HP:0012870 I did not verify this HPO ID.
Abnormal sperm head, base and acrosome — Seen in some patients.
  • Onset and course: Not reported beyond manifesting at adult reproductive age. It is presumably stable. [unverified]
  • Quality of life: No data. Impact is presumably limited to fertility. [unverified]
  • Syndromic features: I found none. CFAP91 variants have not been tied to respiratory ciliary disease in the retrieved sources. I did not check this directly.
  • Frequency: Six of 167 MMAF cases, about 3.6%. The cohort was pre-selected for MMAF.

4. Genetic and molecular information

  • Gene: CFAP91 (MAATS1), 3q13.33. I did not retrieve the HGNC ID. Look it up in HGNC and use the lowercase hgnc: form.
  • Variants: Homozygous deleterious variants, described as loss-of-function (the retrieved summaries did not list the specific variants). Specific variants, ClinVar classifications and gnomAD frequencies were not retrieved.
  • Origin: Germline.
  • Modifier genes, epigenetics and chromosomal abnormalities: None reported.
  • Gene-disease validity: I did not check ClinGen or GenCC. Do not assign a tier without copying one from a source (CGGV:).

5. Environmental information

None known. No infectious agent applies.

6. Mechanism and pathophysiology

Causal chain: 1. Biallelic loss-of-function variants in CFAP91 remove the protein (shown by patient sperm immunostaining). 2. CFAP91 is a calmodulin- and spoke-associated complex (CSC) protein, and it forms a physical and functional partner pair with WDR66. Loss of CFAP91 disrupts CSC and radial spoke assembly. This was shown in humans and in Tetrahymena. 3. In mouse, CFAP91 scaffolds assembly of radial spoke 3 (RS3). Without it, the RS3 proteins CFAP251 and LRRC23 are mislocalized in sperm flagella. 4. Patient sperm show severe central pair complex (CPC) and radial spoke defects by electron microscopy. 5. The axoneme is structurally disorganized, so flagella are absent, short, bent or coiled, and sperm are immotile. This is inferred from the structural findings. 6. Immotile, morphologically abnormal sperm cannot achieve fertilization, which causes male infertility.

Evidence by system: - Human: Six patients, with patient sperm EM and immunostaining. WDR66 was confirmed as a partner. - Trypanosoma brucei: Knockdown of TbCFAP91 impaired flagellar movement and produced CPC defects, as in humans. - Tetrahymena (2022): CFAP91 sits at the base of RS2 and RS3. Knockout impairs RS3 docking and adjacent inner dynein arm assembly, and cilia beat in an uncoordinated manner at greatly reduced frequency. I did not retrieve the PMID. - Mouse (2025): Cfap91 knockout (Nat Commun 16:8238, PMC12423330) causes impaired sperm flagellum formation and male infertility. Proximity labeling identified EFCAB5, and Efcab5 knockout males show reduced sperm motility and fertility.

Suggested terms: - GO: axoneme assembly (GO:0035082), sperm flagellum assembly, cilium movement. I did not verify these IDs. - GO cellular component: motile cilium / sperm flagellum axoneme. - CL: spermatid (CL:0000018), sperm (CL:0000019). I did not verify these IDs.

No omics findings were retrieved.

7. Anatomical structures affected

  • Organ and tissue: Testis and seminiferous epithelium, where spermiogenesis occurs.
  • Cells: Late spermatids and spermatozoa.
  • Subcellular: The sperm flagellar axoneme, including the central pair complex and radial spokes.
  • Lateralization: Bilateral, as expected for a germline disorder.
  • Other systems: None reported.

8. Temporal development

  • Onset: Manifests at adult reproductive age, when infertility is evaluated.
  • Course: Presumably stable. Natural history data are not available.

9. Inheritance and population

  • Inheritance: Autosomal recessive (HP:0000007), from the DO and MalaCards entries.
  • Consanguinity, founder effects and population distribution: Not retrieved. Consanguinity is common in MMAF cohorts generally, but I did not confirm it for these six patients. I assume the condition is rare.
  • Sex: Male-limited phenotype.
  • Prevalence and carrier frequency: Not available. Derive carrier frequency from gnomAD only if a source states it.

10. Diagnostics

  • Semen analysis: Severe asthenozoospermia with MMAF morphology.
  • Electron microscopy of sperm: Shows the CPC and radial spoke defects.
  • Immunostaining: CFAP91 and partners such as WDR66, in patient sperm.
  • Genetic testing: Exome sequencing or an MMAF/male infertility gene panel including CFAP91. Confirm panel inclusion in GTR.
  • Differential: Other MMAF genes, such as DNAH1, CFAP43, CFAP44, CFAP69, AK7 and WDR66, and primary ciliary dyskinesia. I did not check GeneReviews for a chapter.

11. Prognosis

Natural conception is not expected. Life expectancy is not reported as affected, and I found no mortality data.

12. Treatment

  • Established treatment: None specific.
  • ICSI: Intracytoplasmic sperm injection is the usual option for MMAF. Outcomes for CFAP91 patients are not in the retrieved sources.
  • Experimental: I found no trials, gene therapy or drug options.
  • Suggested NCIT: Intracytoplasmic Sperm Injection and Assisted Reproductive Technology terms. Look the CURIEs up with runoak; I have not looked them up.

13. Prevention

  • Genetic counseling: Autosomal recessive risk. Carrier testing of partners and relatives is possible.
  • Other prevention: No primary or environmental measures are known.
  • Prenatal and preimplantation testing: An option once variants are identified. Offspring of an affected man who has ICSI are obligate carriers.

14. Other species and natural disease

  • Orthologs: Mouse Cfap91 (ENSMUSG00000022805); Tetrahymena CFAP91; Trypanosoma TbCFAP91.
  • Natural disease in animals: I found nothing in OMIA and did not search it.

15. Model organisms

Model Finding Evidence source
Mouse Cfap91 knockout Impaired sperm flagellum formation and male infertility. RS3 proteins CFAP251 and LRRC23 are mislocalized. MODEL_ORGANISM
Efcab5 knockout mouse Reduced sperm motility and fertility (interactor). MODEL_ORGANISM
Tetrahymena knockout RS3 docking and inner dynein arm assembly defects, and uncoordinated ciliary beating. MODEL_ORGANISM / IN_VITRO
T. brucei knockdown Impaired flagellar motility and CPC defects. MODEL_ORGANISM / IN_VITRO
  • Fidelity: The mouse recapitulates the male infertility and flagellar defect. I did not retrieve whether it also has non-sperm ciliary phenotypes.
  • Resources: MGI, IMPC and Alliance of Genome Resources entries were not checked.

Key sources

Gaps to close before curation

  1. Confirm OMIM #619177, MONDO:0030926 and the HGNC ID for CFAP91.
  2. Get the exact variants and ClinVar classifications.
  3. Find any additional patient reports and ICSI outcomes.
  4. Fetch the Martinez 2020 abstract and the Tetrahymena paper with just fetch-reference, and take snippets from the cache.
  5. Check ClinGen, GeneReviews and GenCC for a validity tier.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 2
Resolved 2
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 2
On topic 2
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 12
Resolved 12
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 7
Terms named correctly 2
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

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

  • HP:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility
  • HP:0012870 (1 mention) - the report calls it "Abnormal sperm flagella morphology"; HP calls it Vanishing testis

Terms whose name is worth a second look

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

  • HP:0012864 (1 mention) - the report calls it "Teratozoospermia"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names
  • GO:0035082 (1 mention) - the report calls it "GO: axoneme assembly"; GO calls it axoneme assembly
  • CL:0000018 (1 mention) - the report calls it "CL: spermatid"; CL calls it spermatid