Affinage

MKRN3

E3 ubiquitin-protein ligase makorin-3 · UniProt Q13064

Length
507 aa
Mass
55.6 kDa
Annotated
2026-06-10
84 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MKRN3 is a paternally expressed, maternally imprinted RING-finger E3 ubiquitin ligase that acts as a developmental brake on puberty initiation by restraining hypothalamic GnRH secretion (PMID:23738509, PMID:32407292). Its monoallelic expression is enforced by differential DNA methylation, with the maternal allele methylated and the paternal allele active, established shortly after fertilization (PMID:10395905). MKRN3 is expressed in Kiss1 neurons of the arcuate nucleus, where its RING-finger-dependent ubiquitinase activity represses transcription from the KISS1 and TAC3 promoters (PMID:32407292). It silences the GnRH axis through multiple converging mechanisms: it ubiquitinates the methyl-CpG-binding protein MBD3 to block TET2 recruitment and epigenetically repress GNRH1 transcription (PMID:34692086), and it ubiquitinates the poly(A)-binding proteins PABPC1/3/4 to shorten GNRH1 mRNA poly(A) tails and impair translation initiation (PMID:33744966). Hypothalamic MKRN3 protein is high early in life and declines before puberty; this decline is driven by miR-30b, which directly represses MKRN3 via conserved 3'UTR sites, and blocking miR-30 binding sustains MKRN3 and delays puberty (PMID:31697675). Loss-of-function mutations in MKRN3 — frameshift, missense, and promoter variants that reduce its expression or RING-dependent ligase activity — are a common genetic cause of familial central precocious puberty, and genetic ablation of Mkrn3 in mice accelerates puberty onset (PMID:23738509, PMID:34692086, PMID:34421985). Beyond the reproductive axis, MKRN3 functions as a tumor-suppressor E3 ligase, ubiquitinating PABPC1, STAT3, and CSDE1 to restrain cell proliferation (PMID:34143182, PMID:40619404, PMID:42204155).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Before MKRN3's function was known, the basis of its monoallelic expression was unresolved; this established that genomic imprinting via maternal-allele DNA methylation enforces paternal-only expression.

    Evidence Bisulfite methylation mapping and methyltransferase-deficient mouse model with allelic expression analysis

    PMID:10395905

    Open questions at the time
    • Did not connect imprinted expression to any physiological function
    • Methylation dynamics in human hypothalamus not addressed
  2. 2013 High

    The physiological role of MKRN3 was unknown until human genetics linked it to puberty; this established MKRN3 as an inhibitory brake on GnRH secretion whose loss causes central precocious puberty.

    Evidence Whole-exome and Sanger sequencing in families with central precocious puberty plus developmental qPCR of mouse hypothalamus

    PMID:23738509

    Open questions at the time
    • Molecular mechanism of inhibition not defined
    • Cellular site of action within hypothalamus not pinpointed
  3. 2017 Medium

    How MKRN3 acts biochemically was unclear; this provided the first evidence that MKRN3 is an active E3 ligase, polyubiquitinating Nptx1 via its RING finger in the hypothalamus.

    Evidence Reciprocal Co-IP, in vitro ubiquitination assay, and RING-domain deletion in mouse hypothalamus

    PMID:29156706

    Open questions at the time
    • Link between Nptx1 ubiquitination and GnRH secretion not established
    • Single lab, no in vivo loss-of-function for this substrate
  4. 2019 High

    What drives the prepubertal fall in MKRN3 was unknown; this identified miR-30b as a direct post-transcriptional repressor whose blockade sustains MKRN3 and delays puberty.

    Evidence 3'UTR luciferase reporter assays plus central infusion of target-site blockers in juvenile rats with phenotypic readout

    PMID:31697675

    Open questions at the time
    • Upstream control of miR-30b induction unknown
    • Interplay with promoter methylation not resolved
  5. 2019 Medium

    The MKRN3 interactome and its requirement in GnRH neurons were undefined; this catalogued 81 candidate partners and showed MKRN3 knockout in iPSC-derived GnRH neurons did not alter GNRH1, indicating action upstream rather than cell-autonomously in GnRH neurons.

    Evidence AP-MS interactome in HEK cells plus CRISPR knockout in human iPSC-derived GnRH neurons

    PMID:30800097

    Open questions at the time
    • Most interactions unvalidated and possibly overexpression artifacts
    • Negative GNRH1 result not mechanistically explained
  6. 2020 High

    The cellular site and direct transcriptional targets were uncertain; this localized MKRN3 to arcuate Kiss1 neurons and demonstrated RING-dependent repression of KISS1 and TAC3 promoters with conserved cross-species developmental decline.

    Evidence In situ co-localization, KISS1/TAC3 luciferase reporters, in vitro ubiquitination, RING mutagenesis across rodent and primate developmental stages

    PMID:32407292

    Open questions at the time
    • Direct ubiquitination substrate linking to KISS1/TAC3 repression not identified in this study
    • Mechanism of promoter repression incompletely defined
  7. 2020 High

    How MKRN3 silences GNRH1 transcription was unknown; this showed MKRN3 ubiquitinates MBD3 to block TET2 recruitment and demethylation of the GNRH1 promoter, with Mkrn3 knockout accelerating puberty in vivo.

    Evidence Co-IP, in vitro ubiquitination, ChIP, and Mkrn3 knockout mouse with hypothalamic GnRH1 quantification

    PMID:34692086

    Open questions at the time
    • Linkage type of MBD3 ubiquitination not detailed
    • Relative contribution versus translational control unresolved
  8. 2021 High

    A translational mode of GnRH suppression was undefined; this showed MKRN3 ubiquitinates PABPC1/3/4 to shorten GNRH1 poly(A) tails and impair translation initiation complex formation.

    Evidence Co-IP, in vitro ubiquitination, poly(A) tail length assay, translation initiation complex analysis, MS substrate identification

    PMID:33744966

    Open questions at the time
    • In vivo confirmation of GNRH1 translation effect not shown
    • Selectivity for GNRH1 mRNA over global mRNA not fully resolved
  9. 2021 High

    Whether MKRN3 has roles beyond puberty was unexplored; this established MKRN3 as a tumor-suppressor E3 ligase that non-degradatively ubiquitinates PABPC1 to suppress global protein synthesis and proliferation in lung cancer.

    Evidence MS proteomics, in vitro ubiquitination, reconstitution, two knockout mouse models, and xenografts

    PMID:34143182

    Open questions at the time
    • Relationship between non-K48 PABPC1 ubiquitination in cancer and poly(A) effects in hypothalamus unresolved
    • Tissue specificity of tumor-suppressor role not defined
  10. 2021 Medium

    Variant-level mechanism of disease alleles was incompletely characterized; this showed the p.Gly93Ser mutation attenuates auto-ubiquitination and reduces repression of GNRH1, KISS1, and TAC3 promoters, defining it as loss-of-function.

    Evidence In vitro ubiquitination and GNRH1/KISS1/TAC3 luciferase reporter assays

    PMID:34421985

    Open questions at the time
    • No in vivo confirmation of variant effect
    • Single lab in vitro readouts only
  11. 2023 Medium

    Whether MKRN3 shapes hypothalamic structure was unknown; this linked Mkrn3 deletion to increased arcuate dendritic spine density and altered plasticity-gene expression, and identified IGF2BP1 as an interaction partner and NKB as a target.

    Evidence Interactome proteomics, CRISPR knockout mouse with Golgi/spine analysis, iPSC-derived hypothalamic neurons, transcriptomics

    PMID:37092553

    Open questions at the time
    • Causal link between spine changes and puberty timing unproven
    • IGF2BP1 functional consequence of binding not defined
  12. 2023 Medium

    How RING versus non-RING mutations affect activity was unclear; this revealed domain-dependent effects, with RING-domain mutations reducing and extra-RING mutations increasing ubiquitination activity.

    Evidence Western blot ubiquitination assays with multiple mutant constructs

    PMID:36916482

    Open questions at the time
    • Functional consequence of increased activity not tested in vivo
    • Single in vitro method
  13. 2023 Medium

    The contribution of non-coding regulatory variants and promoter methylation to MKRN3 dosage was uncertain; promoter/5'UTR mutations reduce promoter activity and CpG-island methylation falls prepubertally, indicating multilayered control of MKRN3 expression.

    Evidence Luciferase reporter assays in GT1-7/GN11 cells, in silico TF analysis, and bisulfite sequencing across mouse developmental stages

    PMID:29763903 PMID:31636607 PMID:36714607

    Open questions at the time
    • Direct transcription factors controlling expression not validated
    • Causal role of methylation changes not tested by perturbation
  14. 2023 Medium

    Whether MKRN3 acts in the gonads was unknown; this showed gonadal Mkrn3 expression with peripubertal testicular peak in Leydig cells and gonadotropin-responsive regulation, implying a peripheral arm of action.

    Evidence Gonadal RT-qPCR across development, hCG treatment of primary Leydig cells, and in vivo GnRH agonist administration

    PMID:37585624

    Open questions at the time
    • Gonadal substrates and function not defined
    • Phenotypic consequence of gonadal Mkrn3 loss untested
  15. 2025 Medium

    Additional cancer substrates and recruitment mechanisms were undefined; these established that MKRN3 promotes K48-linked STAT3 degradation via the scaffold DLG4 and proteolytically ubiquitinates CSDE1, both restraining tumor proliferation.

    Evidence AP-MS, reciprocal Co-IP, denaturation-IP ubiquitination assays, conditional knockout mouse, and xenografts in lung and ovarian cancer

    PMID:40619404 PMID:42204155

    Open questions at the time
    • Whether these substrates are regulated in the hypothalamus unknown
    • Single lab per substrate
  16. 2025 Low

    An environmental trigger for MKRN3 loss was untested; zearalenone-induced MKRN3 auto-ubiquitination and downregulation increased GnRH production in vitro, with GPER implicated.

    Evidence GT1-7 cell treatment, ubiquitination assay, GnRH quantification, and GPER overexpression rescue

    PMID:40726759

    Open questions at the time
    • Single in vitro system not confirmed in vivo
    • Mechanistic link between auto-ubiquitination and GnRH effect is indirect

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MKRN3's multiple molecular activities (transcriptional repression, MBD3-mediated demethylation block, PABP-mediated translational control, plasticity regulation) are integrated and prioritized within the same Kiss1 neuron to time puberty onset remains unresolved.
  • No unified model assigning relative weight to each repressive mechanism
  • Endogenous signal that initiates the prepubertal MKRN3 decline upstream of miR-30b unknown
  • In vivo substrate-specific rescue experiments lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140096 catalytic activity, acting on a protein 6 GO:0140110 transcription regulator activity 3 GO:0016874 ligase activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 1
Partners
CSDE1IGF2BP1MBD3NPTX1PABPC1PABPC3PABPC4STAT3

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Loss-of-function mutations in MKRN3 (frameshift and missense) cause central precocious puberty in humans; MKRN3 mRNA is high in the arcuate nucleus of prepubertal mice and decreases immediately before puberty, establishing an inhibitory role on GnRH secretion. Whole-exome sequencing, Sanger sequencing, quantitative real-time PCR in mouse hypothalami at different ages The New England journal of medicine High 23738509
1999 The mouse Zfp127 (Mkrn3) gene is differentially methylated with the maternal allele methylated and the paternal allele unmethylated; maternal methylation is established promptly after fertilization prior to syngamy; in methyltransferase-deficient mice Zfp127 is biallelically expressed, demonstrating that methylation enforces paternal-only expression. Bisulfite sequencing / methylation analysis, methyltransferase-deficient mouse model, expression analysis Gene High 10395905
2017 MKRN3 (Mkrn3) functions as an E3 ubiquitin ligase that interacts with and polyubiquitinates Nptx1 (neural pentraxin 1) in the mouse hypothalamus; the RING finger domain of Mkrn3 is required for binding Nptx1 and catalyzing its polyubiquitination; Mkrn3 and Nptx1 show inverse expression patterns in the hypothalamus around puberty initiation. Co-immunoprecipitation, ubiquitination assay, RING finger domain deletion analysis, expression profiling in mouse hypothalamus Oncotarget Medium 29156706
2019 Hypothalamic miR-30b directly represses Mkrn3 via three binding sites in a highly conserved region of the Mkrn3 3' UTR; hypothalamic miR-30b expression increases while Mkrn3 protein decreases during rat postnatal maturation; central infusion of target site blockers preventing miR-30 binding to Mkrn3 3' UTR reversed the prepubertal decline in hypothalamic Mkrn3 protein and delayed female puberty onset. In vitro luciferase reporter assay (3' UTR), central infusion of target site blockers (TSBs) in juvenile rats, western blot, qPCR PLoS biology High 31697675
2019 MKRN3 interacts with 81 high-confidence protein partners identified by mass spectrometry in HEK cells, including proteins involved in insulin signaling, RNA metabolism, and cell-cell adhesion, of which 20 have been previously implicated in puberty timing. MKRN3 knockout in human iPSC-derived GnRH neurons did not alter GNRH1 expression (negative finding). Stable expression in HEK cells followed by mass spectrometry (AP-MS), human iPSC differentiation into GnRH neurons with CRISPR knockout Frontiers in endocrinology Medium 30800097
2020 MKRN3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and represses promoter activity of human KISS1 and TAC3. MKRN3 has intrinsic ubiquitinase (E3 ligase) activity, which is reduced by mutations affecting the RING finger domain; these RING finger mutations also compromise repression of KISS1 and TAC3 promoter activity. MKRN3 expression in the hypothalamus of rats and non-human primates is high early in life and decreases as puberty approaches, independent of sex steroids. In situ hybridization (Mkrn3 and Kiss1 co-localization), luciferase promoter reporter assays (KISS1 and TAC3), in vitro ubiquitination assay, RING finger domain mutagenesis, expression profiling across developmental stages in multiple species The Journal of clinical investigation High 32407292
2020 MKRN3 interacts with and ubiquitinates MBD3 (methyl-CpG binding domain protein 3); this ubiquitination disrupts MBD3 binding to the GNRH1 promoter and prevents recruitment of DNA demethylase TET2, thereby epigenetically silencing GNRH1 transcription. Genetic ablation of Mkrn3 in mice accelerates puberty onset with increased hypothalamic GnRH1 production. Co-immunoprecipitation, in vitro ubiquitination assay, chromatin immunoprecipitation, Mkrn3 knockout mouse model, hypothalamic GnRH1 quantification National science review High 34692086
2021 MKRN3 ubiquitinates three poly(A)-binding proteins (PABPC1, PABPC3, and PABPC4); this ubiquitination attenuates PABP binding to poly(A) tails of mRNA, shortens the poly(A) tail length of GNRH1 mRNA, and compromises formation of the translation initiation complex, thereby suppressing GNRH1 mRNA translation. Co-immunoprecipitation, in vitro ubiquitination assay, poly(A) tail length assay, translation initiation complex analysis, mass spectrometry substrate identification Nucleic acids research High 33744966
2021 MKRN3 functions as a tumor suppressor E3 ubiquitin ligase in non-small cell lung cancer (NSCLC); PABPC1 was identified as a major substrate for MKRN3 via mass spectrometry proteomics. MKRN3 modulates cell proliferation through nonproteolytic (non-K48) ubiquitination of PABPC1 and subsequent suppression of PABPC1-mediated global protein synthesis. MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Mkrn3 knockout mice show increased susceptibility to urethane-induced lung cancer. Mass spectrometry proteomics, in vitro ubiquitination assay, western blot, reconstitution of MKRN3 in knockout cells, MKRN3 knockout mouse (urethane-induced and lung cell-specific), tumor xenograft The Journal of experimental medicine High 34143182
2023 MKRN3 interacts with IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1), identified by proteomics; IGF2BP1 in turn interacts with polyadenylate-binding protein family members. Mkrn3 deletion in a mouse model leads to early puberty onset in female mice and increases dendritic spine number in the arcuate nucleus without altering GnRH neuron morphology. Mkrn3 deletion also results in significant changes in expression of genes controlling hypothalamic development and plasticity in human iPSC-derived hypothalamic neurons. Neurokinin B (NKB) was identified as an Mkrn3 target. Proteomics (interactome analysis), CRISPR knockout mouse model, Golgi staining / spine density analysis, human iPSC-derived hypothalamic neurons with MKRN3 deletion, transcriptomics JCI insight Medium 37092553
2018 A heterozygous 4-nucleotide deletion in the proximal promoter region of MKRN3 (c.-150_-147delTCAG) reduces MKRN3 promoter activity in GT1-7 cells as demonstrated by luciferase reporter assay; in silico analysis predicts loss of a DREAM transcription factor binding site. Luciferase reporter assay in GT1-7 cells, Sanger sequencing, in silico transcription factor binding analysis Neuroendocrinology Medium 29763903
2019 Novel mutations in the proximal promoter region of MKRN3 (-166, -865, -886 nt upstream of TSS) significantly reduce MKRN3 promoter activity in GN11 cells as shown by luciferase reporter assay; a 5'-UTR mutation (+13 nt downstream of TSS) is predicted to destabilize mRNA secondary structure by in silico analysis. Luciferase reporter assay in GN11 cells, Sanger sequencing, in silico mRNA secondary structure analysis Frontiers in endocrinology Medium 31636607
2023 Novel MKRN3 missense mutations within the RING finger domain reduced ubiquitination activity compared to wild-type MKRN3, whereas mutations outside the RING finger domain increased ubiquitination, revealing distinct domain-dependent effects on E3 ligase activity. Western blot ubiquitination assay with mutant and wild-type MKRN3 constructs The Journal of clinical endocrinology and metabolism Medium 36916482
2021 A novel MKRN3 missense mutation (p.Gly93Ser) attenuates MKRN3 auto-ubiquitination and degradation, and reduces inhibition of GNRH1, KISS1, and TAC3 promoter transcriptional activity, establishing it as a loss-of-function mutation that compromises MKRN3's repression of GnRH-related signaling. In vitro ubiquitination assay, luciferase promoter reporter assays (GNRH1, KISS1, TAC3) Frontiers in genetics Medium 34421985
2023 A novel MKRN3 variant (p.Arg327His) attenuates MKRN3 auto-ubiquitination, degradation, and inhibition of GNRH1 transcriptional and translational activity, confirming loss-of-function for this variant. In vitro ubiquitination assay, luciferase reporter assay, translational activity assay American journal of medical genetics. Part A Medium 38054352
2025 MKRN3 (RNF63) directly interacts with STAT3 and promotes its K48-linked polyubiquitination and proteasome-mediated degradation in NSCLC cells; scaffold protein DLG4 recruits RNF63/MKRN3 to STAT3 to facilitate this ubiquitination. In human NSCLC specimens, DLG4 and RNF63 expression levels are inversely correlated with STAT3 levels. Affinity purification mass spectrometry, co-immunoprecipitation, denaturation-IP (ubiquitination assay), immunohistochemistry, cell proliferation assays Cell communication and signaling : CCS Medium 40619404
2023 The CpG island within the Mkrn3 promoter shows significantly lower methylation levels at the pre-pubertal stage compared to pubertal or post-pubertal stages in female mouse hypothalamus, suggesting differential promoter methylation regulates Mkrn3 expression during puberty. In silico analysis identified 14 transcriptional repressors among 29 predicted transcription factor binding sites in the CpG islet region. Bisulfite sequencing of mouse hypothalamus at multiple developmental stages, CpG mapping, in silico transcription factor binding analysis Frontiers in endocrinology Medium 36714607
2023 Mkrn3 mRNA is expressed in testes and ovaries of mice at all ages; testicular Mkrn3 is expressed primarily in the interstitial (Leydig cell) compartment; testicular Mkrn3 expression peaks peripubertally in males and is upregulated by LH/hCG stimulation in a dose-dependent manner in primary Leydig cell cultures; acute GnRH agonist administration increases testicular Mkrn3, while chronic GnRH agonist suppresses it. RT-qPCR in gonads across developmental stages, in vitro hCG treatment of primary Leydig cell cultures, in vivo acute and chronic GnRH agonist administration in adult mice Endocrinology Medium 37585624
2025 MKRN3 (RNF63) ubiquitinates CSDE1 (cold shock domain-containing E1) via proteolytic (degradative) ubiquitination, identified as a major substrate in ovarian cancer cells by mass spectrometry proteomics; MKRN3-mediated CSDE1 degradation suppresses OC cell proliferation; ovary-specific Mkrn3 knockout in mice accelerates P53 inactivation-induced tumorigenesis. Mass spectrometry proteomics, in vitro ubiquitination assay, ovary-specific conditional knockout mouse model, tumor xenograft, in vitro proliferation assays Oncogenesis Medium 42204155
2025 Zearalenone (ZEA) treatment of hypothalamic GT1-7 cells triggers MKRN3 auto-ubiquitination and down-regulation, which leads to increased GnRH production and cell proliferation; GPER (G protein-coupled estrogen receptor) re-localization is associated with this effect and GPER overexpression attenuates ZEA-induced changes. In vitro cell treatment (GT1-7 cells), ubiquitination assay, GnRH quantification, GPER localization analysis, GPER overexpression rescue experiment Toxicology research Low 40726759

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Central precocious puberty caused by mutations in the imprinted gene MKRN3. The New England journal of medicine 367 23738509
2008 A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome. European journal of human genetics : EJHG 100 19066619
2015 A new pathway in the control of the initiation of puberty: the MKRN3 gene. Journal of molecular endocrinology 95 25957321
2020 MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. The Journal of clinical investigation 86 32407292
2019 MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis. Journal of the Endocrine Society 80 31041429
2015 Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. European journal of endocrinology 80 26431553
2014 Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene. The Journal of clinical endocrinology and metabolism 70 24438377
2020 MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3. National science review 68 34692086
2021 MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty. Nucleic acids research 67 33744966
2016 High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic. Neuroendocrinology 64 27225315
2019 Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS biology 62 31697675
2015 Circulating MKRN3 levels decline prior to pubertal onset and through puberty: a longitudinal study of healthy girls. The Journal of clinical endocrinology and metabolism 61 25695892
2014 A novel MKRN3 missense mutation causing familial precocious puberty. Human reproduction (Oxford, England) 59 25316453
2014 MKRN3 mutations in familial central precocious puberty. Hormone research in paediatrics 57 25011910
2017 Molecular Screening of MKRN3, DLK1, and KCNK9 Genes in Girls with Idiopathic Central Precocious Puberty. Hormone research in paediatrics 47 28672280
2021 E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer. The Journal of experimental medicine 44 34143182
2016 Circulating MKRN3 Levels Decline During Puberty in Healthy Boys. The Journal of clinical endocrinology and metabolism 43 27057785
2015 Low Frequency of MKRN3 Mutations in Central Precocious Puberty Among Korean Girls. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 40 25938887
2021 Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations. The Journal of clinical endocrinology and metabolism 39 33383582
2017 Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation. Oncotarget 39 29156706
2015 A missense mutation in MKRN3 in a Danish girl with central precocious puberty and her brother with early puberty. Pediatric research 38 26331766
1996 The human/mouse imprinted genes IGF2, H19, SNRPN and ZNF127 map to two conserved autosomal clusters in a marsupial. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 37 8817070
2015 In silico analysis of a novel MKRN3 missense mutation in familial central precocious puberty. Clinical endocrinology 33 26173472
2019 MKRN3 Interacts With Several Proteins Implicated in Puberty Timing but Does Not Influence GNRH1 Expression. Frontiers in endocrinology 32 30800097
2018 Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region. Neuroendocrinology 29 29763903
2016 Clinical Exome Sequencing Reveals MKRN3 Pathogenic Variants in Familial and Nonfamilial Idiopathic Central Precocious Puberty. Hormone research in paediatrics 28 27931036
2019 Central Precocious Puberty Caused by Novel Mutations in the Promoter and 5'-UTR Region of the Imprinted MKRN3 Gene. Frontiers in endocrinology 25 31636607
2017 MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study. Endocrine 25 28299573
1993 Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome. American journal of medical genetics 25 8266996
1999 Imprinted methylation and its effect on expression of the mouse Zfp127 gene. Gene 24 10395905
2023 MKRN3 inhibits puberty onset via interaction with IGF2BP1 and regulation of hypothalamic plasticity. JCI insight 22 37092553
2020 MKRN3 and KISS1R mutations in precocious and early puberty. Italian journal of pediatrics 22 32228714
2018 Investigation of MKRN3 Mutation in Patients with Familial Central Precocious Puberty. Journal of clinical research in pediatric endocrinology 21 29537379
2016 Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty. Hormone research in paediatrics 21 27798941
2019 Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog. Neuroendocrinology 20 31671431
2021 The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls. Endocrine connections 19 34414898
2016 Males with Paternally Inherited MKRN3 Mutations May Be Asymptomatic. The Journal of pediatrics 18 27640350
2022 MKRN3 role in regulating pubertal onset: the state of art of functional studies. Frontiers in endocrinology 17 36187104
2017 The first Japanese case of central precocious puberty with a novel MKRN3 mutation. Human genome variation 17 28546864
2020 Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome. The Journal of clinical endocrinology and metabolism 16 32480405
2016 Time Course of Central Precocious Puberty Development Caused by an MKRN3 Gene Mutation: A Prismatic Case. Hormone research in paediatrics 16 27424312
2023 Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination. The Journal of clinical endocrinology and metabolism 15 36916482
1996 DNA methylation patterns in human tissues of uniparental origin using a zinc-finger gene (ZNF127) from the Angelman/Prader-Willi region. American journal of medical genetics 15 8669440
2020 Evolutionary Conservation of MKRN3 and Other Makorins and Their Roles in Puberty Initiation and Endocrine Functions. Seminars in reproductive medicine 13 31972861
2019 Low Frequency of MKRN3 and DLK1 Variants in Chinese Children with Central Precocious Puberty. International journal of endocrinology 13 31687022
2018 Association between MKRN3 and LIN28B polymorphisms and precocious puberty. BMC genetics 11 30053798
2019 (Epi)genetic defects of MKRN3 are rare in Asian patients with central precocious puberty. Human genome variation 10 30675365
2019 Evaluation of serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty and premature thelarche. Physiological research 10 31852205
2023 The Key Roles of Makorin RING Finger Protein 3 (MKRN3) During the Development of Pubertal Initiation and Central Precocious Puberty (CPP). Current molecular medicine 9 35748557
2020 Familial central precocious puberty: two novel MKRN3 mutations. Pediatric research 9 33214675
2021 A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study. Frontiers in genetics 8 34421985
2020 A novel heterozygous MKRN3 nonsense mutation in a Chinese girl with idiopathic central precocious puberty: A case report. Medicine 8 32957387
2023 Molecular analysis of MKRN3 gene in Turkish girls with sporadic and familial idiopathic central precocious puberty. Journal of pediatric endocrinology & metabolism : JPEM 7 36883204
2022 Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty. Journal of the Endocrine Society 7 36438546
2021 Conservation of Imprinting and Methylation of MKRN3, MAGEL2 and NDN Genes in Cattle. Animals : an open access journal from MDPI 7 34359112
2018 MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study. Hormone research in paediatrics 7 30269125
2023 The functional study of a novel MKRN3 missense mutation associated with familial central precocious puberty. American journal of medical genetics. Part A 6 38054352
2023 MKRN3 circulating levels in girls with central precocious puberty caused by MKRN3 gene mutations. Journal of endocrinological investigation 6 38112911
2023 Methylation status of hypothalamic Mkrn3 promoter across puberty. Frontiers in endocrinology 5 36714607
2022 MKRN3 circulating levels in Prader-Willi syndrome: a pilot study. Journal of endocrinological investigation 5 35854182
2020 Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty. Journal of pediatric endocrinology & metabolism : JPEM 5 33180049
2021 [Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects]. Problemy endokrinologii 4 34297502
2021 Elevated expression of MKRN3 in squamous cell carcinoma of the head and neck and its clinical significance. Cancer cell international 4 34689784
2025 The scaffold protein DLG4 facilitates RNF63-mediated ubiquitination and degradation of STAT3 in non-small cell lung cancer. Cell communication and signaling : CCS 3 40619404
2016 Conservation of imprinting of MKRN3 and NAP1L5 in rabbits. Animal genetics 3 27091003
2024 The rs6576457 G > A variant in the MKRN3 gene promoter significantly increases the risk of central precocious puberty and lung cancer in Hubei Chinese population. Human molecular genetics 2 39239972
2023 Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG. Endocrinology 2 37585624
2021 Rare mutation in MKRN3 in two twin sisters with central precocious puberty: Two case reports. World journal of clinical cases 2 34877345
2025 A novel model of central precocious puberty disease: Paternal MKRN3 gene-modified rabbit. Animal models and experimental medicine 1 39854156
2025 A Case of Prader-Willi Syndrome With a Deletion Including MAGEL2 , NDN , and MKRN3 , but Excluding SNRPN and SNORD116. American journal of medical genetics. Part A 1 40231584
2025 Genetic variants of the DLK1, KISS1R, MKRN3 genes in girls with precocious puberty. Vavilovskii zhurnal genetiki i selektsii 1 40264804
2024 Genetic Investigation of Regulatory Regions of <italic>MKRN3</italic> and <italic>DLK1</italic> Genes in Children with Central Precocious Puberty. Hormone research in paediatrics 1 39709960
2024 Novel MKRN3 gene mutation associated with central precocious puberty in a Chinese child: a case report. Frontiers in endocrinology 1 39758341
2017 Disruption of NNAT, NAP1L5 and MKRN3 DNA methylation and transcription in rabbit parthenogenetic fetuses. Gene 1 28526651
2026 Divergent epigenetic profile underlie pubertal disorders in MKRN3-associated central precocious puberty and Prader-Willi syndrome: insights from a frameshift variant. World journal of pediatrics : WJP 0 41642464
2026 Use of serum MKRN3 and DLK1 levels in precocious puberty: association with an MKRN3 pathogenic variant. Therapeutic advances in endocrinology and metabolism 0 41732517
2026 MKRN3 variants in central precocious puberty as an example of the complexity to classify missense variants in imprinted genes as pathogenic. Hormone research in paediatrics 0 41950159
2026 The central precocious puberty-associated gene MKRN3 is a tumor suppressor regulating CSDE1 ubiquitination in ovarian cancer. Oncogenesis 0 42204155
2026 Mkrn3, Dlk1, and Mecp2 have distinct hypothalamic expression patterns across pubertal maturation in male and female mice. Journal of the Endocrine Society 0 42238256
2025 Methylation index of the DLK1 and MKRN3 genes in precocious puberty. Vavilovskii zhurnal genetiki i selektsii 0 40556973
2025 Zearalenone induces GnRH neurons activation related to central precocious puberty by triggering MKRN3 auto-ubiquitination and down-regulation. Toxicology research 0 40726759
2025 Phenotypic Variability of Males with Loss-of-Function Mutations of <italic>MKRN3</italic>: A Case Report and Literature Review. Hormone research in paediatrics 0 41264570
2025 Outcomes of Patients With Familial Central Precocious Puberty due to Mutations of MKRN3 Gene After Treatment With Gonadotropin-Releasing Hormone Agonist. International journal of endocrinology 0 41323096
1991 A BsaBI RFLP detected for probe pML34 [D15S9] on chromosome 15q. Nucleic acids research 0 1679924

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