Affinage

PATL2

Protein PAT1 homolog 2 · UniProt C9JE40

Length
543 aa
Mass
61.5 kDa
Annotated
2026-06-10
27 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PATL2 is an oocyte-enriched RNA-binding protein that governs maternal mRNA homeostasis during oocyte growth and meiotic maturation, and its loss causes germinal vesicle or metaphase arrest and female infertility (PMID:28965849, PMID:29661911). It operates within translational-control complexes, interacting with CPEB1 and EIF4E and co-localizing with mRNA-regulatory proteins to repress and store maternal transcripts, and with TUT7 to direct mRNA decay during maturation (PMID:37218508, PMID:39741299); PATL2 mutation reduces mRNA storage in GV oocytes and impedes timely decay in maturing oocytes and early embryos (PMID:39741299). Among its specific targets, PATL2 binds and represses Mos mRNA translation, thereby tuning downstream MAPK signaling and meiotic spindle behavior (PMID:33614659), and it physically stabilizes the cell-cycle regulators CDC23, APC1, and MAD2L1, linking it to APC/C-dependent control of oocyte meiosis (PMID:39741299). PATL2 abundance is set by phosphorylation-triggered ubiquitin-proteasome degradation: phosphorylation at S279 promotes its destruction, and mutations that impair degradation or the modified residue alter PATL2 levels and impair maturation (PMID:33614659, PMID:37218508). Single-cell proteomics of Patl2-null MII oocytes shows broad downregulation of maternal-effect and RNA-binding proteins, and spindle-transfer rescue establishes that the developmental defect is cytoplasmic rather than spindle- or calcium-based (PMID:42062216). Beyond the oocyte, PATL2 has been implicated in granulosa-cell proliferation via PAT-domain-dependent stabilization of ADM2 (PMID:38087182) and, together with PATL1, in transcriptional support of hERG K+ channel expression through interaction with TFIIE (PMID:36608291); an earlier characterization of a PAT1a isoform reported binding to APP/APLP intracellular domains and modulation of their trafficking and processing (PMID:17050537).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2017 High

    Established PATL2 as a human infertility gene by linking biallelic loss-of-function to oocyte GV arrest, answering whether PATL2 is required for human oocyte competence.

    Evidence Patient genetics with Sanger sequencing, plus western blot and immunostaining showing reduced protein

    PMID:28965849

    Open questions at the time
    • Molecular function of PATL2 not defined
    • Cellular pathway through which arrest occurs unknown
  2. 2018 High

    Showed in vivo that PATL2 functions in oocyte mRNA regulation, moving from genetic association to a candidate molecular role through KO phenotype and co-localization with known mRNA-regulatory proteins.

    Evidence Patl2 knockout mouse, oocyte transcriptomics, and co-localization with Cpeb1/Msy2/Ddx6

    PMID:29661911

    Open questions at the time
    • Direct binding partners not biochemically validated
    • Specific target mRNAs not identified
  3. 2021 Medium

    Identified Mos mRNA as a translational target and connected PATL2 dosage to MAPK signaling, while showing PATL2 levels are set by ubiquitin-proteasome turnover.

    Evidence Mutant mRNA microinjection into oocytes, ubiquitination assay in 293T, mRNA-binding and MAPK readouts

    PMID:33614659

    Open questions at the time
    • E3 ligase and degradation signal not identified
    • Single lab
  4. 2023 High

    Defined direct binding to EIF4E and CPEB1 and identified S279 phosphorylation as the trigger for degradation, establishing a regulated translational-repressor mechanism validated in vivo.

    Evidence Co-IP for partners, phosphoproteomics, and S279D phosphomimetic knock-in mouse

    PMID:37218508

    Open questions at the time
    • Kinase phosphorylating S279 unknown
    • Full repertoire of stored transcripts not mapped
  5. 2023 Medium

    Extended PATL2 function beyond the oocyte, showing PAT-domain-dependent stabilization of ADM2 to drive granulosa-cell proliferation.

    Evidence siRNA and PAT-domain deletion in KGN cells plus rat PCOS model

    PMID:38087182

    Open questions at the time
    • Mechanism of ADM2 stabilization unresolved
    • Relationship to oocyte role unclear
  6. 2023 Medium

    Identified a transcriptional role with PATL1 in supporting hERG channel expression via TFIIE, broadening PATL2 function into excitable-cell ion-channel biogenesis.

    Evidence C. elegans screen, RNAi in SH-SY5Y/hiPSC-CMs, patch clamp, luciferase reporter, Co-IP with TFIIE

    PMID:36608291

    Open questions at the time
    • Mechanism of transcriptional facilitation undefined
    • Tissue specificity vs oocyte role unaddressed
  7. 2024 Medium

    Resolved a dual mRNA-fate role (storage via CPEB1, decay via TUT7) and linked PATL2 to cell-cycle control by demonstrating stabilization of CDC23/APC1/MAD2L1 disrupted by patient mutations.

    Evidence Co-IP and mass-spec interactome with WT/mutant PATL2, RNA-seq of human GV oocytes, mouse oocyte western blot

    PMID:39741299

    Open questions at the time
    • Whether PATL2 is a stable APC/C subunit unknown
    • Direct vs indirect stabilization mechanism unresolved
  8. 2026 High

    Established that the developmental defect in PATL2-null oocytes is cytoplasmic, not spindle-based, and quantified the downstream proteomic collapse of maternal-effect proteins.

    Evidence Single-cell proteomics of Patl2-/- MII oocytes and spindle-transfer rescue into WT cytoplasm

    PMID:42062216

    Open questions at the time
    • Direct vs secondary cause of each downregulated protein unclear
    • Temporal order of proteomic changes not resolved
  9. 2026 Medium

    Linked PATL2 loss to dysregulation of HIF-1, TGF-beta, and MAPK signaling and follicular development genes, framing a role in granulosa-oocyte communication.

    Evidence CRISPR Patl2 KO mouse, oocyte transcriptome sequencing, KEGG analysis, mini-gene splicing assay

    PMID:42063164

    Open questions at the time
    • Direct PATL2 targets among dysregulated genes not identified
    • Pathway changes may be downstream consequences

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the kinase and E3 ligase controlling S279-dependent PATL2 turnover, and how PATL2 mechanistically partitions transcripts between storage and decay, remain unresolved.
  • No identified kinase for S279
  • No identified E3 ligase
  • No structural model of PATL2 on target mRNAs

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0045182 translation regulator activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1640170 Cell Cycle 1
Partners
APC1CDC23CPEB1EIF4EMAD2L1TFIIETUT7

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Biallelic loss-of-function mutations in PATL2 (including a homozygous nonsense mutation p.Arg262*) cause oocyte germinal vesicle (GV) arrest and female infertility; western blot in HeLa cells and immunostaining in affected individuals' oocytes demonstrated that the mutations lead to decreased amounts of PATL2 protein. Western blot, immunostaining in patient oocytes, Sanger sequencing, genetic burden test American journal of human genetics High 28965849
2018 Patl2 knockout in mice disturbs oocyte maturation, causing morphological and developmental defects in oocytes and zygotes. Transcriptomic analysis of Patl2-/- oocytes showed deregulated expression of genes involved in oocyte maturation and early embryonic development. Co-localization experiments with Cpeb1, Msy2, and Ddx6 in mouse oocytes suggest Patl2 functions in mRNA regulation during oocyte development. Patl2 knockout mouse model, RNA transcriptomics, immunofluorescence co-localization, whole exome sequencing EMBO molecular medicine High 29661911
2021 PATL2 acts as a translational repressor of Mos mRNA during oocyte maturation. A missense mutation (p.Tyr217Asn) decreased ubiquitination and proteasomal degradation of PATL2, leading to abnormally elevated PATL2 levels, which increased binding of PATL2 to Mos mRNA, suppressed Mos translation, and subsequently impaired MAPK signaling and oocyte meiotic progression. Microinjection of mutant PATL2 mRNA into oocytes caused large polar body, symmetric division, and abnormal spindle. Microinjection of mutant mRNA into oocytes, ubiquitination assay in 293T cells, western blot, mRNA-binding assay, MAPK pathway readouts Frontiers in cell and developmental biology Medium 33614659
2023 PATL2 interacts with EIF4E and CPEB1 in oocytes to regulate maternal mRNA expression. In Patl2-/- mouse GV oocytes, maternal mRNA levels and protein synthesis were reduced. PATL2 is phosphorylated at S279 during oocyte maturation (identified by phosphoproteomics), and the S279D phosphomimetic mutation decreased PATL2 protein level and caused subfertility in knock-in mice via ubiquitin-mediated proteasomal degradation. Co-immunoprecipitation (PATL2-EIF4E, PATL2-CPEB1), Patl2 KO mouse transcriptomics, phosphoproteomics, S279D knock-in mouse model, ubiquitin-proteasome pathway assay Development (Cambridge, England) High 37218508
2023 Knockdown of PATL2 (and PATL1) in SH-SY5Y cells and human iPSC-derived cardiomyocytes decreases hERG K+ channel protein levels and current density, elongates action potential duration. PATL1 and PATL2 interact with TFIIE and facilitate transcription of hERG mRNAs, as shown by dual-luciferase reporter assays. This was initially discovered via a C. elegans forward genetic screen identifying the PATL2 homolog PATR-1 as a regulator of UNC-103 (ERG channel) biogenesis. C. elegans forward genetic screen, RNAi knockdown in SH-SY5Y cells and hiPSC-CMs, electrophysiology (patch clamp), dual-luciferase reporter assay, Co-IP with TFIIE Proceedings of the National Academy of Sciences of the United States of America Medium 36608291
2023 PATL2 promotes proliferation of ovarian granulosa cells by stabilizing ADM2 expression through its PAT structural domain. PATL2 mutant lacking the PAT domain showed normal PATL2 expression but attenuated ADM2 expression and impaired granulosa cell proliferative ability, confirmed in KGN cells and rat PCOS model. siRNA knockdown in KGN cells, PAT-domain deletion mutant transfection, rat PCOS model, western blot, proliferation assay Reproductive sciences Medium 38087182
2024 PATL2 interacts with CPEB1 and TUT7 in human oocytes to maintain mRNA homeostasis (mRNA storage and mRNA decay, respectively). PATL2 mutations decreased mRNA storage in human GV oocytes and impeded mRNA decay during maturation and early embryos. PATL2 also interacts with and stabilizes CDC23 (an APC/C component); mutations in PATL2 (p.V401F/R402W) disrupted interactions with CDC23, APC1, and MAD2L1, implicating PATL2 in cell cycle regulation during oocyte meiosis. Reduced PATL2 lowered protein levels of CDC23, APC1, and MAD2L1 in mouse GV oocytes. Co-immunoprecipitation (PATL2-CPEB1, PATL2-TUT7, PATL2-CDC23/APC1/MAD2L1), RNA sequencing of human GV oocytes, PATL2 interactome by mass spectrometry using WT and mutant variants, western blot in mouse oocytes Cell & bioscience Medium 39741299
2026 Single-cell proteomics of Patl2-/- MII mouse oocytes identified 1508 differentially expressed proteins, with key RNA-binding proteins (including proposed PATL2 interactors Cpeb1 and Eif4e1b) and maternal effect gene products (Zar1, Igf2bp2, Tcl1a, Cdk1, Mos) downregulated, and epigenetic regulators (Zfp57, Trim28) upregulated. The cytoplasmic defects (not spindle or calcium signaling) were responsible for impaired developmental competence, as spindle transfer from Patl2-/- oocytes into wild-type enucleated cytoplasm rescued activation and blastocyst rates to wild-type levels. Single-cell mass spectrometry proteomics (timsTOF, diaPASEF), Patl2-/- KO mouse model, spindle transfer rescue experiment, PIEZO-ICSI, parthenogenetic activation Human reproduction High 42062216
2021 Knockdown of PATL2 by siRNA in granulosa cells (KGN line) significantly prevented apoptosis, suggesting that reduced PATL2 expression paradoxically increases granulosa cell apoptosis (i.e., PATL2 normally promotes apoptosis resistance in granulosa cells). siRNA knockdown in KGN cells, flow cytometry (apoptosis), TUNEL staining Gynecological endocrinology Low 34008465
2006 PAT1a (PATL2) binds directly to APP, APLP1, and APLP2 intracellular domains in vivo and co-localizes with them in trans-Golgi network vesicles or endosomes in primary neurons. PAT1a binds the basolateral sorting signal of APP/APLPs and modulates their transport to the cell surface; overexpression or RNAi knockdown of PAT1a alters APP/APLP surface levels and promotes processing, increasing Abeta secretion. Co-immunoprecipitation, co-localization in primary neurons, RNAi knockdown, overexpression, cell surface ELISA, Abeta measurement The Journal of biological chemistry Medium 17050537
2026 Transcriptome sequencing of Patl2-/- mouse oocytes revealed upregulation of HIF-1 and TGF-beta signaling pathways and MAPK signaling pathway, along with dysregulation of key follicular development genes (Zfp36, Cited1, Fgf8, Id1, Efna1/4), providing evidence that PATL2 regulates mRNA expression of proteins essential for oocyte meiotic progression and granulosa-oocyte communication. CRISPR/Cas9 Patl2 KO mouse model, transcriptome sequencing of oocytes, KEGG pathway analysis, mini-gene splicing assay Journal of ovarian research Medium 42063164

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Biallelic Mutations in PATL2 Cause Female Infertility Characterized by Oocyte Maturation Arrest. American journal of human genetics 124 28965849
2018 PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice. EMBO molecular medicine 81 29661911
2018 Novel mutations in PATL2 cause female infertility with oocyte germinal vesicle arrest. Human reproduction (Oxford, England) 48 29697801
2019 Novel mutations in PATL2: expanding the mutational spectrum and corresponding phenotypic variability associated with female infertility. Journal of human genetics 45 30765866
2006 PAT1a modulates intracellular transport and processing of amyloid precursor protein (APP), APLP1, and APLP2. The Journal of biological chemistry 33 17050537
2020 Novel homozygous mutations in PATL2 lead to female infertility with oocyte maturation arrest. Journal of assisted reproduction and genetics 30 32048119
2023 PATL2 regulates mRNA homeostasis in oocytes by interacting with EIF4E and CPEB1. Development (Cambridge, England) 27 37218508
2021 PATL2 regulated the apoptosis of ovarian granulosa cells in patients with PCOS. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 24 34008465
2021 The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway. Frontiers in cell and developmental biology 21 33614659
2022 Novel mutations in NLRP5 and PATL2 cause female infertility characterized by primarily oocyte maturation abnormality and consequent early embryonic arrest. Journal of assisted reproduction and genetics 20 35091966
2024 Novel PATL2 variants cause female infertility with oocyte maturation defect. Journal of assisted reproduction and genetics 7 38954294
2022 Identification and characterization of a novel homozygous splice site variant of PATL2 causing female infertility due to oocyte germinal vesicle arrest. Frontiers in genetics 7 36072676
2024 Novel splicing mutations in PATL2 and WEE2 cause oocyte degradation and fertilization failure. Journal of assisted reproduction and genetics 6 39476306
2023 DNA topoisomerase 2-associated proteins PATL1 and PATL2 regulate the biogenesis of hERG K+ channels. Proceedings of the National Academy of Sciences of the United States of America 5 36608291
2023 High carrier frequency of pathogenic PATL2 gene mutations predicted in population: a bioinformatics-based approach. Frontiers in genetics 4 37255713
2015 Molecular cloning and characterization of oocyte-specific Pat1a in Rana rugosa frogs. Journal of experimental zoology. Part A, Ecological genetics and physiology 4 26136381
2024 PATL2 mutations affect human oocyte maternal mRNA homeostasis and protein interactions in cell cycle regulation. Cell & bioscience 3 39741299
2023 Reduced PATL2 Impairs the Proliferation of Ovarian Granulosa Cells by Decreasing ADM2 Expression in Patients with PCOS. Reproductive sciences (Thousand Oaks, Calif.) 3 38087182
2025 Identification of novel variants and expansion of the phenotypic spectrum in PATL2, WEE2, and TUBB8 associated with human early embryonic arrest. Journal of assisted reproduction and genetics 2 40399709
2024 Identification of a novel mutation in PATL2 gene associated with the germinal vesicle arrest of oocytes. Biochemistry and biophysics reports 2 39649799
2022 Establishment of pluripotent stem cell line induced by PATL2 heterozygous mutation in patients with oocyte maturation defect-4. Stem cell research 2 35397397
2022 [Oocyte maturation arrest due to compound heterozygous variants of the PATL2 gene in a case]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 35810437
2025 Novel Genetic Variants in PATL2 Corresponding to Different Clinical Phenotypes of Female Infertility. International journal of medical sciences 1 40657385
2026 Single-cell proteomics reveals cytoplasmic defects in Patl2-deficient oocytes rescued by spindle transfer. Human reproduction (Oxford, England) 0 42062216
2026 Identification of two novel PATL2 variants and transcriptome sequencing reveals their role in oocyte maturation. Journal of ovarian research 0 42063164
2025 Identification of a PATL2 missense variant (c.877G>T) disrupting canonical splicing and contributing to female infertility. Frontiers in genetics 0 40704065
2025 [Clinical phenotype and genetic analysis of a patient with Oocyte maturation defect due to a novel variant of PATL2 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 41451498

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