Affinage

C14ORF39

Protein SIX6OS1 · UniProt Q8N1H7

Length
587 aa
Mass
68.2 kDa
Annotated
2026-06-09
21 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C14ORF39/SIX6OS1 is a central element component of the synaptonemal complex (SC) that is essential for homologous chromosome synapsis and the processing of recombination intermediates into crossovers during meiotic prophase I (PMID:27796301). It functions through a direct, multivalent interaction with SYCE1: the SIX6OS1 N-terminus binds and disrupts the SYCE1 core dimer to form a 1:1 complex, while downstream sequences of both proteins form a second distinct interface, and disruption of either interface causes synapsis failure and infertility in mice (PMID:32917591). The SYCE1–SIX6OS1 complex is recruited into the SC central element by SYCE3 (PMID:36635604). Its expression is post-transcriptionally controlled by the splicing factors SRSF1 and BCAS2, which directly bind Six6os1 transcripts and regulate its expression through alternative splicing during meiotic prophase I (PMID:36882745, PMID:39520542). Loss-of-function and protein-destabilizing mutations in C14ORF39 cause meiotic arrest with nonobstructive azoospermia in men and premature ovarian insufficiency in women, phenotypes recapitulated in mutant mice (PMID:33508233, PMID:34718620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2016 High

    Established SIX6OS1 as a bona fide central element SC protein and defined its requirement for synapsis and recombination, answering whether this uncharacterized ORF had a meiotic function.

    Evidence Yeast two-hybrid interaction with SYCE1 plus mouse knockout with cytological meiotic analysis

    PMID:27796301

    Open questions at the time
    • Molecular basis of the SYCE1 interaction not resolved
    • Mechanism linking synapsis defect to failed crossover formation undefined
  2. 2020 High

    Resolved how SIX6OS1 engages SYCE1, showing a two-interface architecture in which the N-terminus disrupts SYCE1 dimerization, and validated each interface genetically.

    Evidence Biochemical interaction studies with targeted mouse deletions/mutations and synapsis analysis

    PMID:32917591

    Open questions at the time
    • High-resolution structure of the assembled complex not reported
    • How the two interfaces cooperate during SC assembly unclear
  3. 2021 High

    Demonstrated that human loss-of-function mutations cause meiotic arrest, showing C14ORF39 is causative for NOA and POI and that truncated proteins fail polycomplex formation despite retaining SYCE1 binding.

    Evidence Whole-exome sequencing across families, co-immunoprecipitation binding assays, cytology, and mouse modeling

    PMID:33508233

    Open questions at the time
    • Genotype–phenotype correlation for partial vs complete asynapsis not fully mapped
  4. 2022 Medium

    Extended the mutational spectrum by showing certain patient variants act by accelerating C14ORF39 protein degradation, identifying protein stability as a disease mechanism.

    Evidence Whole-exome sequencing with protein stability and SC assembly assays

    PMID:34718620

    Open questions at the time
    • Degradation pathway/E3 ligase not identified
    • Single-lab functional assays
  5. 2023 Medium

    Identified SYCE3 as the recruiter of the SYCE1–SIX6OS1 complex into the central element, clarifying how the complex is incorporated into the SC after SYCP1 lattice remodeling.

    Evidence Biochemical reconstitution, separation-of-function mouse mutagenesis, and structural analysis

    PMID:36635604

    Open questions at the time
    • SIX6OS1 interaction was secondary to a SYCE3-focused study
    • Order and stoichiometry of central element assembly incompletely defined
  6. 2023 Medium

    Showed that Six6os1 expression is post-transcriptionally controlled, with SRSF1 directly regulating it via alternative splicing to execute the oocyte prophase I program.

    Evidence Oocyte conditional Srsf1 knockout with immunofluorescence and splicing analysis

    PMID:36882745

    Open questions at the time
    • Six6os1 is one of multiple SRSF1 targets; its specific contribution to the phenotype not isolated
  7. 2024 Medium

    Identified a second splicing regulator, BCAS2, that directly binds Six6os1 pre-mRNA in male germ cells, reinforcing splicing-dependent control of synapsis.

    Evidence CLIP-seq mapping of BCAS2 binding plus conditional knockout with synapsis cytology

    PMID:39520542

    Open questions at the time
    • Whether SRSF1 and BCAS2 act on the same splice events not resolved
    • Single-lab study
  8. 2025 Medium

    Used a C. elegans ortholog to separate SC architecture from crossover regulation, showing a C-terminal domain controls crossover interference and SC molecular organization independent of assembly.

    Evidence C. elegans genetic mutation with 3D-STORM super-resolution microscopy

    PMID:39841849

    Open questions at the time
    • Ortholog assignment to SIX6OS1 is inferred, not established
    • Whether the vertebrate protein has an analogous crossover-interference function untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIX6OS1 mechanistically couples central element assembly to crossover designation and interference in vertebrates remains unresolved.
  • No high-resolution structure of the assembled vertebrate central element
  • Link between SC architecture and crossover interference in mammals undefined
  • Degradation/turnover regulation of C14ORF39 not mapped to a pathway

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1640170 Cell Cycle 1
Partners
BCAS2SRSF1SYCE1SYCE3
Complex memberships
SYCE1-SIX6OS1 complexsynaptonemal complex central element

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 C14ORF39/SIX6OS1 is a component of the central element of the synaptonemal complex (SC). Yeast two-hybrid analysis revealed that SIX6OS1 directly interacts with SYCE1. Loss of SIX6OS1 in mice causes defective chromosome synapsis at meiotic prophase I, arrest at the pachytene-like stage, infertility, and impaired processing of intermediate recombination nodules before crossover formation. Yeast two-hybrid, mouse knockout, cytological analysis of meiotic chromosomes Nature communications High 27796301
2020 SYCE1 undergoes multivalent interactions with SIX6OS1 via two distinct binding interfaces: (1) the N-terminus of SIX6OS1 binds and disrupts SYCE1's core dimeric structure to form a 1:1 complex, and (2) downstream sequences of both proteins provide a second distinct interface. Both interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure, respectively. Mice harboring SYCE1's POF mutation combined with a targeted deletion within SIX6OS1's N-terminus are infertile with failure of chromosome synapsis. Biochemical interaction studies, mouse genetics (targeted deletions/mutations), cellular analysis of synapsis Science advances High 32917591
2021 Homozygous loss-of-function mutations in C14ORF39/SIX6OS1 (frameshift, nonsense, splicing) cause complete or incomplete asynapsis of homologous chromosomes in human male germ cells, resulting in NOA with meiotic arrest, and POI in females. Truncated mutant proteins retain SYCE1 binding but show impaired polycomplex formation between C14ORF39 and SYCE1. The human phenotypes are recapitulated by Six6os1 mutant mice carrying an analogous mutation. Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation (SYCE1 binding assay), cytological meiosis analysis, mouse modeling American journal of human genetics High 33508233
2022 Novel homozygous variants of C14ORF39 found in sporadic POI and NOA patients significantly accelerate C14ORF39 protein degradation, thereby disrupting SC assembly and meiosis. Whole-exome sequencing, functional protein stability assays, SC assembly analysis The Journal of clinical endocrinology and metabolism Medium 34718620
2023 SYCE3 interacts with the CE complexes SYCE1-SIX6OS1 and SYCE2-TEX12, providing a mechanism for their recruitment into the SC central element after SYCE3 remodels the SYCP1 lattice. Biochemical interaction studies, separation-of-function mutagenesis in mice, structural analysis Nature structural & molecular biology Medium 36635604
2023 SRSF1 directly binds and regulates the expression of Six6os1 via alternative splicing to implement the meiotic prophase I program in mouse oocytes; conditional knockout of Srsf1 in oocytes impairs synapsis and recombination. Conditional knockout mouse, immunofluorescence, direct binding assay (SRSF1 to Six6os1 mRNA via alternative splicing analysis) BMC biology Medium 36882745
2024 BCAS2 directly binds Six6os1 pre-mRNA and regulates its expression through alternative splicing in male germ cells; conditional knockout of Bcas2 impairs synapsis during meiotic prophase I, resulting in NOA. CLIP-seq (crosslinking immunoprecipitation and sequencing), conditional knockout mouse, cytological analysis of synapsis Cellular and molecular life sciences : CMLS Medium 39520542
2025 In C. elegans, SYP-4 (a likely ortholog of vertebrate SIX6OS1) has a C-terminal domain whose mutation disrupts crossover interference without disrupting SC assembly, and alters the molecular organization/architecture of the SC as detected by 3D-STORM super-resolution microscopy. C. elegans genetics (mutation), 3D-STORM super-resolution microscopy Science advances Medium 39841849

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. American journal of human genetics 99 35172124
2021 Genetics of ovarian insufficiency and defects of folliculogenesis. Best practice & research. Clinical endocrinology & metabolism 96 34794894
2016 C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility. Nature communications 81 27796301
2021 Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans. American journal of human genetics 69 33508233
2020 Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility. Science advances 41 32917591
2019 Molecular structure of human synaptonemal complex protein SYCE1. Chromosoma 37 30607510
2020 Host genetics influences the relationship between the gut microbiome and psychiatric disorders. Progress in neuro-psychopharmacology & biological psychiatry 34 33130294
2022 Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia. The Journal of clinical endocrinology and metabolism 32 34718620
2019 A molecular model for self-assembly of the synaptonemal complex protein SYCE3. The Journal of biological chemistry 29 31023827
2023 Structural maturation of SYCP1-mediated meiotic chromosome synapsis by SYCE3. Nature structural & molecular biology 22 36635604
2023 SRSF1 regulates primordial follicle formation and number determination during meiotic prophase I. BMC biology 17 36882745
2025 Dynamic molecular architecture of the synaptonemal complex. Science advances 11 39841849
2022 In silico analysis of a novel pathogenic variant c.7G > A in C14orf39 gene identified by WES in a Pakistani family with azoospermia. Molecular genetics and genomics : MGG 9 35305148
2022 Genetic screening in patients with ovarian dysfunction. Clinical genetics 8 36373164
2024 BCAS2 and hnRNPH1 orchestrate alternative splicing for DNA double-strand break repair and synapsis in meiotic prophase I. Cellular and molecular life sciences : CMLS 2 39520542
2025 Common variation in meiosis genes shapes human recombination phenotypes and aneuploidy risk. medRxiv : the preprint server for health sciences 1 40321295
2025 Genetic variants in diminished ovarian reserve and premature ovarian insufficiency: implications for assisted reproductive outcomes. Journal of assisted reproduction and genetics 1 40936058
2025 Single-cell RNA sequencing reveals oocyte-granulosa crosstalk and regulatory networks driving chicken primordial follicle assembly. International journal of biological macromolecules 1 41109371
2026 Common variation in meiosis genes shapes human recombination and aneuploidy. Nature 0 41565805
2026 The synaptonemal complex: structure, function, and clinical implications†. Biology of reproduction 0 42059593
2025 N-carbamylglutamate supplementation improves laying performance of layers by regulating hypothalamic-pituitary-ovarian axis. Frontiers in veterinary science 0 41112153

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