Affinage

ACTL7A

Actin-like protein 7A · UniProt Q9Y615

Length
435 aa
Mass
48.6 kDa
Annotated
2026-04-28
17 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACTL7A is a testis-enriched actin-related protein essential for spermiogenesis, acrosome biogenesis, and male fertility. During spermatid development, ACTL7A localizes dynamically to the nucleus, subacrosomal space, and postacrosomal perinuclear theca, where it is required for acroplaxome-associated F-actin assembly and stable anchoring of the acrosome to the nuclear envelope; loss of ACTL7A abolishes subacrosomal F-actin structures, causes acrosomal detachment, small-head sperm morphology through defective acrosome-acroplaxome-manchette complex formation, and loss of intranuclear HDAC1/HDAC3 localization (PMID:36734600, PMID:37667331, PMID:35863052, PMID:38464253). ACTL7A participates in a perinuclear theca protein complex with FNDC8, CCIN, ZPBP, and ARPM1, and its stability depends on FNDC8 (PMID:41169243, PMID:35921706). Homozygous or compound heterozygous loss-of-function mutations in ACTL7A cause total fertilization failure in humans by disrupting acrosomal ultrastructure, reducing PLCζ expression and localization in sperm, and abolishing oocyte activation competence (PMID:32923619, PMID:34727571).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1999 Medium

    Identification of ACTL7A as an intronless actin-related gene on chromosome 9q31, clustered with ACTL7B, established it as a novel member of the actin-related protein family expressed broadly in adult tissues.

    Evidence cDNA selection and direct genomic sequencing with linkage mapping

    PMID:10373328

    Open questions at the time
    • No functional data; expression breadth not reconciled with later testis-enrichment findings
    • No protein-level characterization
  2. 2012 Medium

    Demonstration that ACTL7A is upregulated via the PKA pathway during capacitation and that anti-ACTL7A antibodies block fertilization established ACTL7A as a functionally important sperm surface/structural component required for fertility.

    Evidence Western blot and immunostaining of capacitated mouse sperm; in vitro agglutination assays; active immunization fertility assays in mice

    PMID:22386842 PMID:23211711

    Open questions at the time
    • Molecular mechanism of PKA-dependent upregulation undefined
    • Whether antibody effects reflect surface exposure or secondary disruption unclear
    • No genetic loss-of-function model yet
  3. 2020 High

    A homozygous ACTL7A missense mutation in a human family, recapitulated in a knock-in mouse, linked ACTL7A directly to acrosomal ultrastructural integrity and PLCζ-dependent oocyte activation, establishing it as a cause of total fertilization failure.

    Evidence WES in infertile patient, knock-in mouse model, TEM, immunofluorescence, western blot, artificial oocyte activation rescue

    PMID:32923619

    Open questions at the time
    • Mechanism by which ACTL7A controls PLCζ expression/localization unknown
    • Single family — allelic spectrum not yet defined
  4. 2021 Medium

    Identification of compound heterozygous ACTL7A variants causing the same phenotype confirmed that biallelic loss-of-function is a recurrent genetic cause of oocyte activation deficiency and fertilization failure in humans.

    Evidence WES, Sanger validation, TEM, immunofluorescence, western blot, calcium ionophore rescue in a second family

    PMID:34727571

    Open questions at the time
    • Still limited to two families
    • Carrier frequency and population-level contribution unknown
  5. 2022 High

    A series of studies using knock-in/knockout mouse models and proteomics defined the precise structural role of ACTL7A: it anchors to the acroplaxome, and specific mutations (e.g., G402S) cause the protein to be discharged in cytoplasmic droplets, resulting in bubble-shaped acrosomes; ACTL7A also forms a complex with ZPBP to facilitate zona pellucida binding.

    Evidence Knock-in and knockout mouse models, TEM, IP-LC/MS interactome, Co-IP with ZPBP, IVF/ICSI functional assays

    PMID:35863052 PMID:35921706 PMID:36574082

    Open questions at the time
    • Direct binding interface between ACTL7A and ZPBP uncharacterized
    • How ACTL7A is recruited to the acroplaxome molecularly remains unclear
  6. 2023 High

    Knockout studies revealed that ACTL7A is absolutely required for subacrosomal F-actin formation and that its loss causes small-head sperm through defective acrosome-acroplaxome-manchette complex assembly, with proteomics implicating PI3K/AKT/mTOR-mediated autophagy inhibition and PDLIM1 accumulation as downstream consequences.

    Evidence Actl7a KO mouse, F-actin staining, live/fixed imaging, TEM, TMT quantitative proteomics, western blot

    PMID:36593593 PMID:36734600 PMID:37667331

    Open questions at the time
    • Whether ACTL7A directly polymerizes or nucleates F-actin is unknown
    • PI3K/AKT/mTOR pathway link is correlative from proteomics, not validated by pathway perturbation
    • PDLIM1 role in manchette development not independently confirmed
  7. 2025 Medium

    Identification of FNDC8 and CCIN as direct interaction partners that stabilize ACTL7A protein placed ACTL7A within a hierarchical perinuclear theca protein network required for sperm head morphogenesis.

    Evidence Co-immunoprecipitation, Fndc8 KO mouse model, immunofluorescence, western blot

    PMID:41169243

    Open questions at the time
    • Stoichiometry and assembly order of the PT complex not defined
    • Whether FNDC8 stabilizes ACTL7A directly or through a scaffold is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether ACTL7A has intrinsic actin-like polymerization or ATPase activity, the structural basis of its integration into the acroplaxome, the mechanism by which it controls PLCζ retention in sperm, and whether it substitutes for canonical actin in nuclear chromatin-remodeling complexes during spermiogenesis.
  • No biochemical reconstitution of ACTL7A polymerization or ATPase activity
  • No crystal or cryo-EM structure
  • Chromatin remodeler interaction model is computational only
  • PLCζ retention mechanism completely undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005856 cytoskeleton 3 GO:0005634 nucleus 2
Pathway
R-HSA-1474165 Reproduction 5
Partners
ARPM1CCINFNDC8PLCZ1ZPBP
Complex memberships
Perinuclear theca complex (FNDC8–CCIN–ACTL7A–ZPBP)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 ACTL7A encodes a 435-amino-acid actin-like protein (predicted molecular mass 48.6 kDa) expressed in a wide variety of adult tissues; it is an intronless gene located on chromosome 9q31 in a head-to-head orientation with ACTL7B on a common 8-kb HindIII fragment. cDNA selection, direct genomic sequencing, linkage mapping Genomics Medium 10373328
2012 During capacitation in mouse spermatozoa, ACTL7A expression is upregulated via the PKA pathway and its localization undergoes remodeling, indicating it is an essential component of the capacitation process. Western blot and indirect immunostaining of capacitated vs. non-capacitated mouse sperm; PKA pathway analysis Fertility and sterility Medium 23211711
2012 Anti-ACTL7A antibodies cause agglutination of mouse and human spermatozoa in vitro and markedly reduce sperm fertilizing capacity; active immunization of mice with ACTL7A protein significantly reduces fertility, establishing ACTL7A as a target of immunologic infertility. In vitro sperm agglutination assay, fertility assay in immunized mice, mass spectrometry identification, indirect immunostaining Fertility and sterility Medium 22386842
2020 A homozygous missense mutation in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm, and results in reduced expression and abnormal localization of PLCζ in sperm, linking ACTL7A to oocyte activation competence and early embryonic arrest. Whole-exome sequencing, knock-in mouse model, transmission electron microscopy (TEM), immunofluorescence, western blot, artificial oocyte activation rescue Science advances High 32923619
2021 Compound heterozygous loss-of-function variants in ACTL7A cause ultrastructural defects in the acrosome and perinuclear theca, and significantly reduce PLCζ protein expression in sperm, leading to oocyte activation deficiency and total fertilization failure. Whole-exome sequencing, Sanger sequencing, TEM, immunofluorescence, western blotting, AOA rescue (calcium ionophore A23187) Human reproduction (Oxford, England) Medium 34727571
2022 ACTL7A forms a complex with zona pellucida binding protein (ZPBP), and loss of ACTL7A in knockout mice alters ZPBP localization in sperm, reducing sperm–zona pellucida binding ability and contributing to fertilization failure. Co-immunoprecipitation, immunofluorescence, knockout mouse model, IVF/ICSI functional assay Biochemical and biophysical research communications Medium 35921706
2022 A pathogenic missense variant in ACTL7A (p.Gly402Ser) causes the mutant protein to fail to attach to the acroplaxome and to be discharged in cytoplasmic droplets, resulting in absence of ACTL7A in epididymal spermatozoa, acrosome detachment from the nuclear membrane (bubble-shaped acrosomes), and discharge of PLCζ, leading to total fertilization failure. Knock-in mouse model, TEM, immunofluorescence, immunoprecipitation followed by LC-MS, western blot, AOA rescue Molecular human reproduction High 35863052
2022 A novel homozygous missense mutation (p.D75A) in ACTL7A leads to protein degradation in sperm, acrosomal ultrastructural defects and irregular perinuclear theca, and abnormal localization and reduced expression of PLCζ, causing fertilization failure after ICSI. WES, 3D structural modeling, immunofluorescence, western blot, TEM Molecular genetics and genomics: MGG Medium 36574082
2023 ACTL7A is dynamically localized within the nucleus and subacrosomal space in developing spermatids and later in postacrosomal regions; knockout of Actl7a causes complete loss of subacrosomal filamentous actin (F-actin) structures, indicating ACTL7A is required for acroplaxome-associated F-actin formation and acrosomal attachment integrity. Actl7a knockout mouse model, immunofluorescence (including F-actin staining), live/fixed imaging of developing spermatids Molecular human reproduction High 36734600
2023 Loss of ACTL7A in knockout mice causes small-head sperm due to defective acrosome-acroplaxome-manchette complex formation; proteomics revealed that ACTL7A loss activates autophagy inhibition via the PI3K/AKT/mTOR pathway, leading to PDLIM1 accumulation and hindered manchette development. Actl7a KO mouse model, immunofluorescence, TEM, tandem mass tag quantitative proteomics, western blot, ICSI-AOA rescue Reproductive biology and endocrinology: RB&E Medium 37667331
2023 Homozygous nonsense variant in ACTL7A causes increased thickness of the perinuclear matrix and detachment of the acrosome from the nuclear envelope as observed by TEM, further confirming ACTL7A's structural role in perinuclear theca integrity. WES, TEM, immunofluorescence Clinical genetics Medium 36593593
2024 ACTL7A is present in the nucleus of developing spermatids; in the absence of ACTL7A, intranuclear localization of HDAC1 and HDAC3 is lost, implicating ACTL7A in chromatin regulatory complex function during spermiogenesis. In silico modeling further suggests ACTL7A can substitute for actin/ACTL6A in binding HSA domains of INO80 and SWI/SNF nucleosome remodeling complexes. Actl7a KO mouse model, immunofluorescence for HDAC1/HDAC3 nuclear localization, testis transcriptomic analysis, AI-facilitated in silico structural modeling bioRxivpreprint Low 38464253
2025 ACTL7A interacts with the perinuclear theca protein FNDC8 and with CCIN during spermiogenesis; depletion of FNDC8 destabilizes ACTL7A protein, placing ACTL7A downstream of FNDC8 in a PT protein interaction network required for sperm head morphogenesis. Co-immunoprecipitation, Fndc8 knockout mouse model, immunofluorescence, western blot Zoological research Medium 41169243
2025 ACTL7A interacts with ARPM1 (ACTRT3) as shown by co-immunoprecipitation; ARPM1 deficiency does not directly ablate ACTL7A but ACTL7A is part of the PT cytoskeletal complex that also includes ACTRT1, ACTRT2, and ZPBP. Co-immunoprecipitation from mouse testis/sperm lysates bioRxivpreprint Low bio_10.1101_2025.03.27.645694

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest. Science advances 78 32923619
2021 Novel bi-allelic variants in ACTL7A are associated with male infertility and total fertilization failure. Human reproduction (Oxford, England) 34 34727571
1999 Cloning, mapping, and expression of two novel actin genes, actin-like-7A (ACTL7A) and actin-like-7B (ACTL7B), from the familial dysautonomia candidate region on 9q31. Genomics 30 10373328
2023 Testis-specific actin-like 7A (ACTL7A) is an indispensable protein for subacrosomal-associated F-actin formation, acrosomal anchoring, and male fertility. Molecular human reproduction 21 36734600
2022 Pathogenic variant in ACTL7A causes severe teratozoospermia characterized by bubble-shaped acrosomes and male infertility. Molecular human reproduction 21 35863052
2023 Novel variants in ACTL7A and PLCZ1 are associated with male infertility and total fertilization failure. Clinical genetics 17 36593593
2012 Anti-ACTL7a antibodies: a cause of infertility. Fertility and sterility 16 22386842
2023 Loss of ACTL7A causes small head sperm by defective acrosome-acroplaxome-manchette complex. Reproductive biology and endocrinology : RB&E 15 37667331
2022 Actl7a deficiency in mice leads to male infertility and fertilization failure. Biochemical and biophysical research communications 13 35921706
2016 Immune Infertility Should Be Positively Diagnosed Using an Accurate Method by Monitoring the Level of Anti-ACTL7a Antibody. Scientific reports 12 26957350
2022 Sperm-specific protein ACTL7A as a biomarker for fertilization outcomes of assisted reproductive technology. Asian journal of andrology 11 35532568
2022 A novel homozygous mutation in ACTL7A leads to male infertility. Molecular genetics and genomics : MGG 11 36574082
2012 Dynamic alterations in the expression and localization of ACTL7a during capacitation in mouse spermatozoa. Fertility and sterility 11 23211711
2023 Novel ACTL7A variants in males lead to fertilization failure and male infertility. Andrology 7 37991128
2019 Genetic Polymorphisms within The Intronless ACTL7A and ACTL7B Genes Encoding Spermatogenesis-Specific Actin-Like Proteins in Japanese Males. International journal of fertility & sterility 6 31310081
2024 Novel Nuclear Roles for Testis-Specific ACTL7A and ACTL7B Supported by In Vivo Characterizations and AI Facilitated In Silico Mechanistic Modeling with Implications for Epigenetic Regulation in Spermiogenesis. bioRxiv : the preprint server for biology 1 38464253
2025 Perinuclear theca protein FNDC8 interacts with CCIN and ACTL7A to ensure proper sperm head shaping during spermiogenesis. Zoological research 0 41169243