Affinage

CCIN

Calicin · UniProt Q13939

Length
588 aa
Mass
66.6 kDa
Annotated
2026-04-28
24 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCIN encodes Calicin, a structural cytoskeletal protein of the sperm perinuclear theca (PT) that self-associates and interacts with inner acrosomal membrane protein SPACA1, nuclear envelope components, ACTL7A, and FNDC8 to form an IAM-PT-NE scaffold essential for sperm head morphogenesis during spermiogenesis (PMID:35793634, PMID:41169243). Calicin is required for proper nuclear condensation and head shaping; loss of CCIN in knockout mice causes surface subsidence of sperm heads, DNA damage, and fertilization failure due to inability to adhere to the zona pellucida (PMID:35793634, PMID:36546111). Homozygous and compound heterozygous loss-of-function mutations in CCIN cause human teratozoospermia with severe sperm head malformation and male infertility, which can be bypassed by ICSI (PMID:36546111, PMID:36527329).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2021 Low

    Identifying that Calicin undergoes oxidative post-translational modifications mediated by 2-Cys peroxiredoxins placed CCIN within the redox-regulated sperm cytoskeletal proteome, though its functional significance remained unclear.

    Evidence Mass spectrometry-based oxPTM profiling of bull sperm after pharmacological PRDX inhibition

    PMID:34884692

    Open questions at the time
    • Single proteomics study without functional follow-up on CCIN specifically
    • Role of oxidative modifications on Calicin function not tested
    • Not confirmed in human sperm
  2. 2022 High

    Direct demonstration that Calicin self-associates and bridges the inner acrosomal membrane (via SPACA1) to the nuclear envelope established CCIN as a central organizer of the perinuclear theca scaffold, and Ccin-knockout mice revealed its necessity for sperm head shaping, DNA integrity, and fertilization.

    Evidence Reciprocal Co-IP, immunofluorescence, live imaging, and Ccin-knockout mouse phenotyping

    PMID:35793634

    Open questions at the time
    • Structural basis of Calicin self-association unknown
    • Mechanism linking PT disruption to DNA damage not resolved
    • Whether Calicin directly contacts the zona pellucida or acts indirectly is unclear
  3. 2022 High

    Human genetic evidence confirmed that CCIN mutations cause teratozoospermia and male infertility, and zona adhesion assays pinpointed failure of sperm-zona binding as the proximate cause, with ICSI providing functional rescue.

    Evidence Patient exome sequencing, mouse knock-in models of disease variants, zona adhesion assays, ICSI rescue experiments

    PMID:36546111

    Open questions at the time
    • Identity of the zona receptor engaged by Calicin-dependent surface structures unknown
    • Whether PT structural defects alter other surface proteins mediating zona binding not determined
  4. 2023 Low

    An additional patient harboring a homozygous CCIN missense variant with sperm head nuclear subsidence reinforced the genotype–phenotype relationship but did not add new mechanistic insight.

    Evidence Sanger sequencing and sperm morphological analysis in a single patient

    PMID:36527329

    Open questions at the time
    • Single case report without functional validation of variant pathogenicity
    • No protein-level or rescue data provided
  5. 2025 Medium

    Placing CCIN in a ternary interaction network with FNDC8 and ACTL7A showed that upstream PT factors stabilize Calicin protein levels, and their loss phenocopies CCIN deficiency with acrosome detachment and head collapse.

    Evidence Co-immunoprecipitation and Fndc8-knockout mouse model with immunofluorescence and Western blot

    PMID:41169243

    Open questions at the time
    • Whether FNDC8 directly stabilizes CCIN or acts via ACTL7A is unresolved
    • Stoichiometry and assembly order of the FNDC8-CCIN-ACTL7A complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of Calicin self-association, the mechanism by which PT disruption causes DNA damage, and the identity of zona pellucida receptors dependent on Calicin-organized surface architecture remain unresolved.
  • No structural model of Calicin or its oligomeric assembly exists
  • Causal link between PT scaffold loss and DNA damage is correlative
  • Downstream zona-binding partners not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-1474165 Reproduction 3
Partners
ACTL7AFNDC8SPACA1

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. It 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, DNA damage, and failure of fertilization. Co-immunoprecipitation, immunofluorescence, live imaging/fractionation, knockout mouse model with defined phenotypic readout Cell reports High 35793634
2022 Homozygous missense and compound heterozygous mutations in CCIN cause teratozoospermia with severe sperm head malformation and markedly reduced Calicin protein levels. Mutant spermatozoa (human and mouse models) fail to adhere to the zona pellucida, identified as the major mechanistic reason for CCIN-mutant sperm-derived infertility. ICSI bypasses this defect and restores fertility. Patient exome sequencing, Sanger sequencing, immunofluorescence, ultrastructural analysis, mouse knock-in models expressing disease-associated variants, zona adhesion assay, ICSI rescue Science bulletin High 36546111
2025 FNDC8 (a testis-enriched PT protein) physically interacts with CCIN and ACTL7A during spermiogenesis; depletion of FNDC8 destabilizes both CCIN and ACTL7A proteins, leading to acrosome detachment and sperm head surface collapse, placing CCIN within a PT protein-interaction network essential for sperm head morphogenesis. Co-immunoprecipitation, knockout mouse model, immunofluorescence, Western blot Zoological research Medium 41169243
2021 CCIN (Calicin) is among bull sperm actin cytoskeleton proteins that undergo oxidative post-translational modifications (oxPTMs) mediated by 2-Cys peroxiredoxins (PRDXs) under basal conditions, as revealed by inhibition of 2-Cys PRDXs with Conoidin A. Proteomic/mass spectrometry analysis of oxPTMs after pharmacological inhibition of 2-Cys PRDXs in sperm International journal of molecular sciences Low 34884692
2022 FSIP2 mutations in asthenoteratozoospermic patients are associated with downregulated expression of CCIN in spermatozoa, placing CCIN downstream of FSIP2 in acrosome biogenesis and sperm morphogenesis. Whole exome sequencing of patients, immunofluorescence, proteomics (LC-MS/MS), co-immunoprecipitation for FSIP2 interactors 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 maintaining sperm nuclear structure. Sanger sequencing of patient, sperm morphological analysis 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 97 20530655
2004 Limbal stem cell deficiency following topical mitomycin C treatment of conjunctival-corneal intraepithelial neoplasia. American journal of ophthalmology 74 15126170
2005 Topical 0.002% mitomycin C for the treatment of conjunctival-corneal intraepithelial neoplasia and squamous cell carcinoma. Cornea 49 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 22 36546111
2022 FSIP2 plays a role in the acrosome development during spermiogenesis. Journal of medical genetics 17 35654582
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
2024 Genetic etiological spectrum of sperm morphological abnormalities. Journal of assisted reproduction and genetics 12 39417902
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