Affinage

PMFBP1

Polyamine-modulated factor 1-binding protein 1 · UniProt Q8TBY8

Length
1007 aa
Mass
117.5 kDa
Annotated
2026-06-10
25 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PMFBP1 is a testis-specific scaffold protein of the sperm head-neck junction that physically couples the sperm head to the flagellum, and its loss causes acephalic spermatozoa syndrome in both humans and mice (PMID:30032984, PMID:30298696). At this junction it cooperates with SUN5 and SPATA6, and integrates into a multiprotein head-neck complex that also includes CEP250, whose own interaction with PMFBP1/SUN5 is lost upon CEP250 disruption (PMID:30032984, PMID:39726222). Beyond its structural role, PMFBP1 acts in a regulatory axis during spermatogenesis: it associates with the chaperonin subunit CCT3 and with HDAC3, and its loss reduces HDAC3 expression with downstream downregulation of the E3 ligase factors RNF151 and RNF133 (PMID:37423931). Disease-causing alleles — missense, nonsense, splice-site, and truncating mutations — converge mechanistically on destabilization or loss of PMFBP1 protein in sperm (PMID:33484382, PMID:41462896, PMID:39668357), establishing PMFBP1 as a causative gene for acephalic spermatozoa syndrome.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2018 High

    Established PMFBP1 as a structural scaffold at the sperm head-tail junction by showing it cooperates with SUN5 and SPATA6 and that its loss produces acephalic spermatozoa, defining a molecular basis for head-tail decapitation.

    Evidence Pmfbp1 knockout mice, co-IP with SUN5/SPATA6, and whole-exome sequencing of human patients, with independent immunofluorescence localization and KO replication plus proteomics

    PMID:30032984 PMID:30298696

    Open questions at the time
    • Direct binding interfaces/stoichiometry of the SUN5-SPATA6-PMFBP1 assembly not resolved
    • Mechanism connecting PMFBP1 loss to Golgi vesicle transport changes unclear
  2. 2023 Medium

    Extended PMFBP1 from a purely structural protein to a node in a gene-regulatory axis by identifying CCT3 and HDAC3 as interactors and linking PMFBP1 loss to reduced HDAC3 and downstream RNF151/RNF133.

    Evidence IP-MS, co-IP, immunoblotting, RT-qPCR, and proteomics/transcriptomics of Pmfbp1-/- mouse testis (single lab)

    PMID:37423931

    Open questions at the time
    • Not independently replicated
    • Direct vs indirect nature of the PMFBP1-HDAC3 functional link unresolved
    • How a junction scaffold modulates HDAC3 levels mechanistically unknown
  3. 2024 Medium

    Placed CEP250 in the same head-neck junction complex as PMFBP1, broadening the membership of the structural assembly.

    Evidence Reciprocal co-IP, immunofluorescence, and CRISPR-Cas9 knock-in mice (single lab)

    PMID:39726222

    Open questions at the time
    • Whether CEP250 binds PMFBP1 directly or via SUN5 not established
    • Spatial architecture of the full complex unknown
  4. 2025 Medium

    Defined how disease alleles act mechanistically, showing missense, nonsense, splice-site, and truncating mutations destabilize or abolish PMFBP1 protein in sperm.

    Evidence Western blot of patient sperm, in vitro mutant expression, cycloheximide chase, MG132 proteasome assays, and in vitro splicing models across multiple patient studies

    PMID:33484382 PMID:39668357 PMID:41462896

    Open questions at the time
    • Each allele characterized in a single lab
    • Genotype-phenotype correlation across mutation classes not systematized
  5. 2025 Low

    Implicated additional partners (ODF1/ODF2, CCDC188) by co-depletion, hinting at broader structural dependencies but without direct interaction proof for PMFBP1.

    Evidence Western blotting and immunofluorescence of patient sperm

    PMID:35860846 PMID:41004021

    Open questions at the time
    • No direct PMFBP1 interaction assay performed for CCDC188 or ODF1/ODF2
    • Single method (Western/IF), no orthogonal validation
    • Cause vs consequence of expression changes unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural architecture and biochemical mechanism by which PMFBP1 simultaneously scaffolds the head-neck junction and influences HDAC3-dependent gene regulation remain unresolved.
  • No structural model of the PMFBP1-containing junction complex
  • Direct binding partners vs co-dependent proteins not fully distinguished
  • Mechanism coupling structural scaffolding to transcriptional/regulatory output unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2
Pathway
R-HSA-1474165 Reproduction 2
Partners
CCT3CEP250HDAC3SPATA6SUN5
Complex memberships
sperm head-neck junction complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 PMFBP1 cooperates with SUN5 and SPATA6 at the sperm head-tail junction; disruption of Pmfbp1 in male mice causes infertility due to acephalic spermatozoa and loss of this cooperative interaction, establishing PMFBP1 as a structural scaffold linking the sperm head to the tail. Pmfbp1 knockout mice (loss-of-function), co-immunoprecipitation/interaction studies with SUN5 and SPATA6, whole-exome sequencing in human patients American journal of human genetics High 30032984
2018 PMFBP1 localizes to the head-flagella junction region of sperm, and its absence (in patients with biallelic truncating mutations) is associated with acephalic spermatozoa; Pmfbp1 KO mice recapitulate the phenotype. Label-free quantitative proteomics of KO testicular sperm showed enrichment of differentially expressed proteins in Golgi vesicle transport, suggesting PMFBP1 affects Golgi-related processes during head-neck junction formation. Immunofluorescence staining for localization, Pmfbp1 knockout mouse generation, label-free quantitative proteomics of testicular sperm Clinical genetics High 30298696
2023 PMFBP1 interacts with HDAC3 and CCT3 (chaperonin-containing TCP1 subunit 3); loss of Pmfbp1 in mice reduces HDAC3 expression, which in turn downregulates RNF151 and RNF133, defining a PMFBP1–CCT3–HDAC3–RNF151/RNF133 molecular axis during spermatogenesis. Immunoprecipitation combined with mass spectrometry (IP-MS), co-immunoprecipitation, immunoblotting, immunohistochemistry, RT-qPCR, proteomics and transcriptomics of Pmfbp1-/- mouse testis Journal of assisted reproduction and genetics Medium 37423931
2021 A homozygous missense mutation in PMFBP1 (c.301A>C, p.T101P) causes reduced PMFBP1 protein expression in sperm, confirmed by Western blotting of patient sperm and in vitro expression of the mutant construct, demonstrating that missense mutations can destabilize PMFBP1 protein. Western blotting of patient sperm, immunofluorescence, in vitro expression of mutant PMFBP1 construct Journal of assisted reproduction and genetics Medium 33484382
2022 Truncating mutations in PMFBP1 reduce expression of outer dense fiber proteins ODF1 and ODF2, indicating PMFBP1 regulates ODF1/ODF2 expression as part of sperm tail structural assembly. Western blotting of sperm from patient with compound heterozygous PMFBP1 mutations Molecular genetics & genomic medicine Low 35860846
2024 CEP250 physically interacts with SUN5 and PMFBP1 at the sperm neck region; a loss-of-function mutation in CEP250 reduces this interaction, placing CEP250 in the same head-neck junction complex as PMFBP1. Co-immunoprecipitation, immunofluorescence, CRISPR-Cas9 knock-in mice Andrology Medium 39726222
2025 A nonsense mutation in PMFBP1 (c.2641C>T, p.Arg881Ter) produces a truncated protein with significantly altered stability (assessed by cycloheximide chase and MG132 proteasome inhibitor assays), causing absence of PMFBP1 in sperm and acephalic spermatozoa syndrome. Western blot, cycloheximide chase assay, MG132 proteasome inhibitor assay, Sanger sequencing, transmission electron microscopy Biomedicines Medium 41462896
2024 A homozygous splice site mutation (c.2089-1G>T) in PMFBP1 causes deletion of 4 bp from exon 15, abolishing PMFBP1 protein expression in sperm, confirmed by in vitro splicing model, RT-PCR and Sanger sequencing. Western blotting, immunofluorescence, in vitro splice-site mutation model, RT-PCR, Sanger sequencing Basic and clinical andrology Medium 39668357
2025 Loss of CCDC188 protein in patients is accompanied by co-depletion of SUN5 and PMFBP1 in sperm, suggesting CCDC188 functions in the same structural complex at the sperm head-neck junction as PMFBP1. Western blotting and immunofluorescence of patient sperm Journal of assisted reproduction and genetics Low 41004021

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Mutations in PMFBP1 Cause Acephalic Spermatozoa Syndrome. American journal of human genetics 97 30032984
2011 Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis and rheumatism 94 22170508
2018 Biallelic mutations in PMFBP1 cause acephalic spermatozoa. Clinical genetics 45 30298696
2022 Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits. Nature communications 37 35546142
2022 Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia. Andrology 33 36017582
2020 Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human. Molecular genetics & genomic medicine 31 32410354
2023 Transcriptome and proteome analyses reveal the mechanisms involved in polystyrene nanoplastics disrupt spermatogenesis in mice. Environmental pollution (Barking, Essex : 1987) 26 38061432
2022 BmPMFBP1 regulates the development of eupyrene sperm in the silkworm, Bombyx mori. PLoS genetics 24 35312700
2024 Genetic etiological spectrum of sperm morphological abnormalities. Journal of assisted reproduction and genetics 17 39417902
2021 Genetic basis of acephalic spermatozoa syndrome, and intracytoplasmic sperm injection outcomes in infertile men: a systematic scoping review. Journal of assisted reproduction and genetics 15 33452591
2021 A novel homozygous missense mutation of PMFBP1 causes acephalic spermatozoa syndrome. Journal of assisted reproduction and genetics 14 33484382
2022 Novel mutations of PMFBP1 in a man with acephalic spermatozoa defects. Molecular genetics & genomic medicine 9 35860846
2022 Compound heterozygous mutations in PMFBP1 cause acephalic spermatozoa syndrome: A case report. World journal of clinical cases 6 36579083
2023 Identification of Potentially Novel Molecular Targets of Endometrial Cancer Using a Non-Biased Proteomic Approach. Cancers 5 37760635
2023 Loss of PMFBP1 Disturbs Mouse Spermatogenesis by Downregulating HDAC3 Expression. Journal of assisted reproduction and genetics 4 37423931
2020 Prevention of multiple system atrophy using human bone marrow-derived mesenchymal stem cells by reducing polyamine and cholesterol-induced neural damages. Stem cell research & therapy 4 32127052
2024 A homozygous loss-of-function mutation in CEP250 is associated with acephalic spermatozoa syndrome in humans. Andrology 3 39726222
2019 [Advances in the molecular genetic studies of acephalic spermatozoa syndrome]. Zhonghua nan ke xue = National journal of andrology 3 32233213
2025 Novel CCDC188 variants cause acephalic spermatozoa syndrome with poor intracytoplasmic sperm injection outcome. Journal of assisted reproduction and genetics 1 41004021
2024 Pathogenesis of acephalic spermatozoa syndrome caused by PMFBP1 mutation. Basic and clinical andrology 1 39668357
2022 [Gender differences of genetic etiology in the incidence of major depressive disorder among Han freshmen]. Zhonghua yi xue za zhi 1 35599408
2026 Genetic diversity of infertile males in India. Journal of assisted reproduction and genetics 0 41483127
2025 Establishment and clinical significance of genetic factor screening method for patients with nonobstructive azoospermia based on whole exon sequencing technology. Translational andrology and urology 0 40376536
2025 A Novel Homozygous Mutation in PMFBP1 Associated with Acephalic Spermatozoa Defects. Biomedicines 0 41462896
2024 [Clinical characteristics and genetic analysis of a patient with Acephalic spermatozoa syndrome due to variant of PMFBP1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 38818563

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