Affinage

CCIN

Calicin · UniProt Q13939

Length
588 aa
Mass
66.6 kDa
Annotated
2026-06-09
24 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCIN encodes Calicin, a cytoskeletal organizing protein of the sperm perinuclear theca (PT) that shapes the sperm head and protects nuclear integrity during spermiogenesis (PMID:35793634). Calicin self-associates and binds multiple PT components, and bridges the inner acrosomal membrane protein SPACA1 to nuclear envelope components, assembling an integrated IAM-PT-NE structural unit; its loss causes surface subsidence of the condensing sperm head, DNA damage, and fertilization failure (PMID:35793634). Calicin functions within an FNDC8-CCIN-ACTL7A complex required for PT structural integrity, since loss of FNDC8 destabilizes both Calicin and ACTL7A and leads to acrosome detachment and sperm head collapse (PMID:41169243). In humans, biallelic CCIN mutations reduce Calicin protein levels and cause severe sperm head malformation; the resulting failure of mutant spermatozoa to adhere to the zona pellucida is the principal mechanistic basis of CCIN-associated male infertility, and ICSI rescues fertilization (PMID:36546111).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2022 High

    Established Calicin as the structural organizing hub of the perinuclear theca by showing it self-associates and links the inner acrosomal membrane to the nuclear envelope, defining how the sperm head is shaped and the nucleus protected.

    Evidence Co-IP, immunofluorescence, fractionation, and Ccin knockout mouse with sperm head shaping, DNA damage, and fertilization readouts

    PMID:35793634

    Open questions at the time
    • Structural basis of how Calicin physically couples IAM to NE not resolved
    • Stoichiometry and architecture of the PT assembly hub undefined
    • Whether DNA damage is direct or secondary to head collapse unclear
  2. 2022 High

    Connected CCIN to a defined human disease, showing biallelic mutations cause teratozoospermia and identifying failed zona pellucida adhesion as the mechanistic cause of infertility, which ICSI bypasses.

    Evidence Patient whole-exome sequencing, knock-in mouse models, zona adhesion assay, and ICSI rescue

    PMID:36546111

    Open questions at the time
    • Molecular basis linking head malformation to loss of zona adhesion not defined
    • How specific missense variants destabilize Calicin protein unknown
  3. 2023 Low

    Reinforced the head-shaping role by linking an additional CCIN missense variant to the nuclear subsidence phenotype in patients.

    Evidence Sanger sequencing and morphological assessment in a male infertility case

    PMID:36527329

    Open questions at the time
    • Single case report with no functional experiments
    • Variant pathogenicity not validated in vivo
  4. 2025 Medium

    Placed Calicin within an FNDC8-CCIN-ACTL7A complex, clarifying that Calicin stability and PT integrity depend on partner proteins.

    Evidence Co-IP, Fndc8 knockout mouse, and Western blot for protein stability

    PMID:41169243

    Open questions at the time
    • Single-lab finding without independent replication
    • Direct binding interfaces within the complex not mapped
    • Whether Calicin stabilizes its partners reciprocally untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical mechanism by which Calicin organizes PT assembly and the role of its oxidative modification remain open.
  • No structural model of Calicin or its PT contacts
  • Functional consequence of PRDX-mediated oxidative PTMs on Calicin untested
  • Relationship between FSIP2-dependent regulation and Calicin function undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005635 nuclear envelope 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1474165 Reproduction 2
Partners
ACTL7AFNDC8SPACA1
Complex memberships
FNDC8-CCIN-ACTL7A complexperinuclear theca

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 Calicin (CCIN) interacts with itself (self-association) and many other perinuclear theca (PT) components, suggesting it serves as an organizing center of PT assembly. Calicin also interacts with inner acrosomal membrane (IAM) protein SPACA1 and nuclear envelope (NE) components to form an 'IAM-PT-NE' structure. Loss of Calicin (Ccin knockout) causes surface subsidence of sperm heads during nuclear condensation and leads to DNA damage and failure of fertilization in mice. Co-immunoprecipitation, immunofluorescence, live imaging/fractionation, knockout mouse model with phenotypic readout (sperm head shaping, fertilization failure, DNA damage) Cell reports High 35793634
2022 Homozygous missense and compound heterozygous mutations in CCIN cause severe sperm head malformation (teratozoospermia) with markedly reduced Calicin protein levels in spermatozoa. Mutant spermatozoa from both mice and human patients fail to adhere to the zona pellucida, identified as the major mechanistic reason for CCIN-mutant sperm-derived infertility. Mouse models expressing disease-associated CCIN variants recapitulate the human phenotype. Patient whole-exome sequencing with Sanger validation, immunofluorescence assays on patient and mouse spermatozoa, ultrastructural morphological analysis, zona adhesion assay, ICSI rescue experiment, knock-in mouse models Science bulletin High 36546111
2025 FNDC8 (a testis-enriched PT protein) physically interacts with CCIN and ACTL7A during spermiogenesis. Genetic disruption of Fndc8 destabilizes both CCIN and ACTL7A proteins, resulting in acrosome detachment and sperm head collapse, placing CCIN within a FNDC8-CCIN-ACTL7A complex required for PT structural integrity and sperm head morphogenesis. Co-immunoprecipitation, Fndc8 knockout mouse model, immunofluorescence, Western blot for protein stability Zoological research Medium 41169243
2021 Calicin (CCIN) is among a group of actin cytoskeleton proteins in bull sperm that undergoes oxidative post-translational modifications (oxPTMs) mediated by 2-Cys peroxiredoxins (PRDXs) under control conditions, as revealed by inhibition of PRDXs with Conoidin A. 2-Cys PRDX inhibition (Conoidin A treatment), proteomics/mass spectrometry to detect oxidative PTMs on sperm proteins International journal of molecular sciences Low 34884692
2022 FSIP2 mutations in asthenoteratozoospermic patients lead to downregulated expression of CCIN in spermatozoa, placing CCIN downstream of FSIP2 in a pathway regulating acrosome biogenesis and sperm morphology. Whole exome sequencing, Western blot and immunofluorescence in patient spermatozoa, co-immunoprecipitation (for FSIP2 interactions), proteomics Journal of medical genetics Low 35654582
2023 A novel homozygous missense variant in CCIN causes male infertility with an abnormal sperm head nuclear subsidence phenotype, consistent with Calicin's role in sperm head shaping. Sanger sequencing, clinical genetic analysis, spermatozoa morphological assessment Clinical genetics Low 36527329

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology 144 9400769
2010 Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications. The British journal of ophthalmology 98 20530655
2004 Limbal stem cell deficiency following topical mitomycin C treatment of conjunctival-corneal intraepithelial neoplasia. American journal of ophthalmology 75 15126170
2005 Topical 0.002% mitomycin C for the treatment of conjunctival-corneal intraepithelial neoplasia and squamous cell carcinoma. Cornea 50 15829803
2020 Exome sequencing reveals novel causes as well as new candidate genes for human globozoospermia. Human reproduction (Oxford, England) 43 31985809
1991 Site-specific recombinase genes in three Shigella subgroups and nucleotide sequences of a pinB gene and an invertible B segment from Shigella boydii. Journal of bacteriology 37 2061288
2020 Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player. Human genetics 30 33108537
2022 The perinuclear theca protein Calicin helps shape the sperm head and maintain the nuclear structure in mice. Cell reports 28 35793634
2004 A case of conjunctiva-cornea intraepithelial neoplasia successfully treated with topical mitomycin C and interferon alfa-2b in cycles. Cornea 26 14701965
2022 Mutations in CCIN cause teratozoospermia and male infertility. Science bulletin 24 36546111
2022 FSIP2 plays a role in the acrosome development during spermiogenesis. Journal of medical genetics 18 35654582
2024 Genetic etiological spectrum of sperm morphological abnormalities. Journal of assisted reproduction and genetics 17 39417902
2020 Saikosaponin a contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 13 33421903
2016 Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality. EMBO molecular medicine 13 27737899
2023 Transcriptomic signatures for human male infertility. Frontiers in molecular biosciences 11 37670815
2021 Effect of 2-Cys Peroxiredoxins Inhibition on Redox Modifications of Bull Sperm Proteins. International journal of molecular sciences 11 34884692
2020 Saikosaponin d contributed to cancer chemotherapy induced neutropenia therapy by promoting neutrophil differentiation via activation CBL-dependent ERK pathway. Pharmacological research 11 32822868
2022 Globozoospermia: A Case Report and Systematic Review of Literature. The world journal of men's health 10 36047070
2020 Identification of a novel deletion mutation in DPY19L2 from an infertile patient with globozoospermia: a case report. Molecular cytogenetics 8 32582379
2018 Embryos derived from couples with consanguineous marriages with globozoospermia should be screened for gender or DPY19L2 deletion. Andrologia 7 30584989
1997 The site-specific recombinase encoded by pinD in Shigella dysenteriae is due to the presence of a defective Mu prophage. Microbiology (Reading, England) 6 9202481
2023 Novel homozygous variant of CCIN causes male infertility owing to the abnormal sperm head with a nuclear subsidence phenotype. Clinical genetics 3 36527329
2008 [Effects of carbon-coated iron nanocrystals combined with epirubicin on HepG-2 cells and its acute toxicity in mice]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 2 18250036
2025 Perinuclear theca protein FNDC8 interacts with CCIN and ACTL7A to ensure proper sperm head shaping during spermiogenesis. Zoological research 0 41169243

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