Affinage

ARMC12

Armadillo repeat-containing protein 12 · UniProt Q5T9G4

Length
340 aa
Mass
38.6 kDa
Annotated
2026-06-09
7 papers in source corpus 5 papers cited in narrative 7 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

ARMC12 is a mitochondrial peripheral membrane protein that acts as an adherence factor driving mitochondrial sheath assembly during spermiogenesis (PMID:33536340). In testicular germ cells it scaffolds mitochondria together by binding VDAC2 and VDAC3 and interacting with MIC60, TBC1D21, and GK2, with TBC1D21 acting as an obligate mediator of the ARMC12–VDAC interaction (PMID:33536340). Loss of ARMC12 blocks mitochondrial elongation at the interlocking step, producing abnormal mitochondrial coiling along the flagellum, reduced sperm motility, and male sterility (PMID:33536340); biallelic loss-of-function mutations in humans cause asthenozoospermia with absent mitochondrial sheath and associated midpiece and axonemal defects, establishing a conserved role (PMID:35534203). Independent of this germline function, ARMC12 has been characterized in neuroblastoma, where it interacts with RBBP4 to promote PRC2-mediated transcriptional repression of tumor suppressor genes (PMID:30026490) and partners with MYC within liquid condensates to upregulate nucleoporin genes (NUP62, NUP93, NUP98) and nuclear pore complex biogenesis, enhancing invasion and metastasis (PMID:41510169).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2018 Medium

    Established the first molecular function for ARMC12 in cancer, defining it as a chromatin regulator that physically partners with RBBP4 to enable PRC2-mediated silencing of tumor suppressors.

    Evidence Co-immunoprecipitation and cell-penetrating inhibitory peptide blocking ARMC12–RBBP4 interaction with downstream gene expression readout in neuroblastoma cells

    PMID:30026490

    Open questions at the time
    • Single-lab study without reciprocal in vivo validation
    • Does not define how ARMC12 is recruited to PRC2 target loci
    • Relationship to ARMC12's mitochondrial role left unaddressed
  2. 2021 High

    Defined ARMC12 as a mitochondrial adherence factor and mapped its scaffold complex, resolving how mitochondria are physically linked during sheath formation.

    Evidence FLAG knock-in mice, reciprocal co-immunoprecipitation, Armc12-null phenotyping, and TBC1D21-null epistasis in testicular germ cells

    PMID:33536340

    Open questions at the time
    • Structural basis of VDAC2/VDAC3 scaffolding not resolved
    • Biochemical activity of ARMC12 beyond protein scaffolding unknown
  3. 2021 High

    Ordered the assembly hierarchy by showing TBC1D21 is an obligate mediator of the ARMC12–VDAC interaction in vivo.

    Evidence Tbc1d21-null mice with co-immunoprecipitation from testicular germ cells

    PMID:33536340

    Open questions at the time
    • Whether TBC1D21 acts catalytically or structurally in mediating the interaction is unresolved
  4. 2022 High

    Translated the mouse phenotype to human disease, confirming ARMC12 loss causes asthenozoospermia with mitochondrial sheath and midpiece defects.

    Evidence Whole-exome sequencing of patients plus parallel CRISPR-Cas9 Armc12-knockout mice with TEM and immunofluorescence

    PMID:35534203

    Open questions at the time
    • Mechanism linking sheath loss to additional axonemal and membrane defects not dissected
  5. 2026 Medium

    Extended the disease phenotype to a single MMAF patient, showing ARMC12 loss redistributes mitochondrial outer-membrane proteins to a punctate pattern without reducing their levels.

    Evidence Whole-exome/Sanger sequencing with immunofluorescence, Western blot, SEM and TEM in a single patient carrying c.686G>A

    PMID:41971121

    Open questions at the time
    • Single patient/family limits generalizability
    • Does not establish whether protein redistribution is cause or consequence of sheath disorganization
  6. 2026 Medium

    Uncovered a second oncogenic mechanism whereby ARMC12 cooperates with MYC in liquid condensates to drive nucleoporin expression and nuclear pore biogenesis supporting invasion and metastasis.

    Evidence Co-IP, mass spectrometry, ChIP, dual-luciferase reporter, overexpression/silencing, RNA-seq, and nude mouse xenograft in neuroblastoma

    PMID:41510169

    Open questions at the time
    • Single-lab study not independently replicated
    • Biophysical basis of condensate formation and ARMC12's contribution to it undefined
    • Connection between the RBBP4/PRC2 and MYC/nucleoporin functions unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intrinsic biochemical activity of ARMC12 and how a single protein partitions between mitochondrial sheath scaffolding and nuclear/chromatin oncogenic functions remain unknown.
  • No catalytic activity assigned
  • No structural model of ARMC12 or its complexes
  • Tissue-specific switch between germline and tumor functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-4839726 Chromatin organization 1
Partners
GK2MIC60MYCRBBP4TBC1D21VDAC2VDAC3
Complex memberships
PRC2

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 ARMC12 is a mitochondrial peripheral membrane protein that functions as an adherence factor between mitochondria. In testicular germ cells, ARMC12 physically interacts with mitochondrial proteins MIC60, VDAC2, and VDAC3, as well as TBC1D21 and GK2, using VDAC2 and VDAC3 as scaffolds to link mitochondria together during mitochondrial sheath formation in spermiogenesis. FLAG-tagged knock-in mice, co-immunoprecipitation, Armc12-null mouse phenotypic analysis, TBC1D21-null mouse epistasis Proceedings of the National Academy of Sciences of the United States of America High 33536340
2021 TBC1D21 is required for the interaction between ARMC12 and VDAC proteins in vivo; in Tbc1d21-null mice, the ARMC12–VDAC interaction is disrupted, establishing TBC1D21 as an obligate mediator of this scaffold complex. Tbc1d21-null mice, co-immunoprecipitation from testicular germ cells Proceedings of the National Academy of Sciences of the United States of America High 33536340
2021 Absence of ARMC12 prevents mitochondrial elongation at the mitochondrial interlocking step during spermiogenesis, causing abnormal mitochondrial coiling along the flagellum, reduced sperm motility, and male sterility. Armc12-null mouse generation, sperm motility assay, electron microscopy of flagellar ultrastructure Proceedings of the National Academy of Sciences of the United States of America High 33536340
2018 ARMC12 physically interacts with retinoblastoma binding protein 4 (RBBP4) to facilitate the formation and activity of polycomb repressive complex 2 (PRC2), resulting in transcriptional repression of tumor suppressive genes in neuroblastoma cells. Co-immunoprecipitation, cell-penetrating inhibitory peptide blocking ARMC12–RBBP4 interaction, downstream gene expression assays Nature communications Medium 30026490
2022 Biallelic loss-of-function mutations in ARMC12 in humans cause asthenozoospermia with multiple midpiece defects including absent mitochondrial sheath, absent central pair, scattered or forked axoneme, and incomplete plasma membrane, confirming the conserved mitochondrial sheath assembly function of ARMC12 in humans. Whole-exome sequencing, Sanger sequencing, Armc12-knockout mice (CRISPR-Cas9), transmission electron microscopy, immunofluorescence Journal of medical genetics High 35534203
2026 In a patient with MMAF carrying a homozygous ARMC12 c.686G>A variant, ARMC12 loss causes severe disorganization of mitochondrial sheath structures and loss of axonemal elements; mitochondrial outer membrane proteins COX IV and TOM20 shift from a continuous distribution along the mitochondrial sheath to a discontinuous punctate pattern without significant reduction in total protein levels. Whole exome sequencing, Sanger sequencing, immunofluorescence, Western blot, scanning electron microscopy, transmission electron microscopy Translational andrology and urology Medium 41971121
2026 ARMC12 interacts with MYC within liquid condensates in neuroblastoma cells and upregulates nucleoporin-encoding targets (NUP62, NUP93, NUP98), promoting nuclear pore complex biogenesis to facilitate nuclear trafficking of oncogenic effectors and enhance invasion and metastasis. Co-immunoprecipitation, mass spectrometry, chromatin immunoprecipitation, dual-luciferase reporter assay, gene overexpression/silencing, RNA sequencing, nude mouse xenograft Theranostics Medium 41510169

Source papers

Stage 0 corpus · 7 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 ARMC12 regulates spatiotemporal mitochondrial dynamics during spermiogenesis and is required for male fertility. Proceedings of the National Academy of Sciences of the United States of America 65 33536340
2018 Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. Nature communications 47 30026490
2021 ARMC Subfamily: Structures, Functions, Evolutions, Interactions, and Diseases. Frontiers in molecular biosciences 25 34912852
2022 Biallelic mutations in ARMC12 cause asthenozoospermia and multiple midpiece defects in humans and mice. Journal of medical genetics 10 35534203
2023 FKBP5 genetic variants are associated with respiratory- and sleep-related parameters in Chinese patients with obstructive sleep apnea. Frontiers in neuroscience 6 37274192
2026 Dual targeting of AMRC12 and Malassezia globosa disrupts MYC liquid condensates-driven nuclear pore complex biogenesis in neuroblastoma. Theranostics 0 41510169
2026 Homozygous ARMC12 variant causes multiple morphological abnormalities of the sperm flagella. Translational andrology and urology 0 41971121

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