Details for: MKRN3

Gene ID: 7681

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: MKRN3

Ensembl ID: ENSG00000179455

Description: makorin ring finger protein 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • neural cell CL0002319
    CSI 4.89
    rCSI 18.45%
    PRS 83.29
  • inhibitory interneuron CL0000498
    CSI 4.66
    rCSI 10.75%
    PRS 87.92
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 4.62
    rCSI 5.34%
    PRS 88.39
  • monocyte CL0000576
    CSI 4.57
    rCSI 8.26%
    PRS 95.44
  • retinal bipolar neuron CL0000748
    CSI 4.39
    rCSI 8.21%
    PRS 88.54
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 4.12
    rCSI 5.13%
    PRS 83.47
  • interneuron CL0000099
    CSI 4.09
    rCSI 8.21%
    PRS 90.41
  • glutamatergic neuron CL0000679
    CSI 3.83
    rCSI 7.86%
    PRS 85.15
  • glioblast CL0000030
    CSI 3.67
    rCSI 5.86%
    PRS 88.68
  • Bergmann glial cell CL0000644
    CSI 3.18
    rCSI 4.36%
    PRS 88.83
  • VIP GABAergic cortical interneuron CL4023016
    CSI 3.16
    rCSI 3.77%
    PRS 85.6
  • retinal ganglion cell CL0000740
    CSI 3.04
    rCSI 6.72%
    PRS 86.93
  • retinal cone cell CL0000573
    CSI 2.81
    rCSI 4.52%
    PRS 88.32
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 2.8
    rCSI 5.08%
    PRS 90.1
  • contractile cell CL0000183
    CSI 2.52
    rCSI 7.44%
    PRS 94.76
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.5
    rCSI 3.22%
    PRS 86.53
  • cardiac neuron CL0010022
    CSI 2.38
    rCSI 7.61%
    PRS 93.65
  • neural progenitor cell CL0011020
    CSI 1.85
    rCSI 8.13%
    PRS 85.61
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.82
    rCSI 3.21%
    PRS 85.06
  • amacrine cell CL0000561
    CSI 1.8
    rCSI 5.23%
    PRS 88.25
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.4
    rCSI 2.35%
    PRS 85.75
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 1.28
    rCSI 4.02%
    PRS 88.1
  • GABAergic neuron CL0000617
    CSI 0.99
    rCSI 3.32%
    PRS 84.07
  • glial cell CL0000125
    CSI 0.86
    rCSI 3.27%
    PRS 89.42
  • H2 horizontal cell CL0004218
    CSI 0.72
    rCSI 3.57%
    PRS 90.24
  • indirect pathway medium spiny neuron CL4023029
    CSI 0.46
    rCSI 11.01%
    PRS 83.23
  • direct pathway medium spiny neuron CL4023026
    CSI 0.36
    rCSI 8.73%
    PRS 83.37

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [MKRN3](/details-gene/7681) (Makorin Ring Finger Protein 3) is a protein-coding gene located on chromosome 15q11.2, a region associated with the imprinted neurodevelopmental disorder Prader-Willi syndrome ([Link](https://doi.org/10.1093/hmg/8.5.783)). Functionally, [MKRN3](/details-gene/7681) acts as a probable E3 ubiquitin-protein ligase, playing a role in [protein polyubiquitination](/details-go/GO0000209). Expression data highlights its significant role within the central nervous system, with high specificity in various neuronal populations, including [neural cell](/details-cell/CL0002319)s and [inhibitory interneuron](/details-cell/CL0000498)s. Clinically, loss-of-function mutations in the paternally inherited [MKRN3](/details-gene/7681) allele are a well-established cause of familial central precocious puberty, indicating its function as a critical inhibitor of pubertal onset ([Link](https://doi.org/10.1056/nejmoa1302160)). ## Cellular Roles and Expression Landscape The expression profile of [MKRN3](/details-gene/7681) firmly establishes its importance within the nervous system. **Overall**, the gene shows its highest significance in a broad range of neural cell types. It is a particularly strong marker for [neural cell](/details-cell/CL0002319)s (CSI: 4.89), [inhibitory interneuron](/details-cell/CL0000498)s (CSI: 4.66), and developing [neuroblast (sensu Nematoda and Protostomia)](/details-cell/CL0000338)s (CSI: 4.62). Its prominence extends to specialized neurons such as [retinal bipolar neuron](/details-cell/CL0000748)s, [pvalb GABAergic cortical interneuron](/details-cell/CL4023018)s, and [glutamatergic neuron](/details-cell/CL0000679)s, suggesting a widespread role in neuronal function and maintenance. The gene's activity is also noted in glial cell lineages, including [Bergmann glial cell](/details-cell/CL0000644)s and [differentiation-committed oligodendrocyte precursor](/details-cell/CL4023059)s. Interestingly, outside of the nervous system, [MKRN3](/details-gene/7681) demonstrates significant expression in [monocyte](/details-cell/CL0000576)s (CSI: 4.57), ranking among the top associated cell types. This suggests a potential, though less characterized, secondary role for [MKRN3](/details-gene/7681) in the innate immune system. The specific expression pattern, heavily skewed towards neuronal and, to a lesser extent, monocytic lineages, points to specialized functions rather than ubiquitous housekeeping roles. ## Pathways and Molecular Function The primary molecular function of [MKRN3](/details-gene/7681) is its [ubiquitin protein ligase activity](/details-go/GO0061630), which facilitates the attachment of ubiquitin chains to substrate proteins, a process known as [protein ubiquitination](/details-go/GO0016567). This activity is characteristic of proteins containing a RING-type zinc finger domain, which binds metal ions ([metal ion binding](/details-go/GO0046872)) and is critical for mediating the transfer of ubiquitin. This function suggests that [MKRN3](/details-gene/7681) regulates cellular processes by targeting specific proteins for degradation by the proteasome. In addition to its enzymatic role, [MKRN3](/details-gene/7681) is annotated with [protein binding](/details-go/GO0005515) and [RNA binding](/details-go/GO0003723) capabilities. Its localization within the [ribonucleoprotein complex](/details-go/GO1990904) further suggests that it may participate in post-transcriptional gene regulation, potentially linking protein degradation pathways with RNA metabolism. This dual functionality could be critical in the precise spatio-temporal control of protein expression required for complex processes like neuronal development and the timing of puberty. ## Research Directions The established role of [MKRN3](/details-gene/7681) as a key negative regulator of puberty, combined with its molecular functions, provides a strong basis for further investigation. **Proposed Testable Hypotheses:** 1. As an E3 ubiquitin ligase highly expressed in neurons, [MKRN3](/details-gene/7681) likely targets and promotes the degradation of one or more key puberty-promoting proteins within the hypothalamus. Loss-of-function mutations would therefore lead to the accumulation of these factors, causing premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. 2. The [RNA binding](/details-go/GO0003723) capacity of [MKRN3](/details-gene/7681) suggests it may function within a ribonucleoprotein complex to repress the translation of mRNAs encoding activators of puberty, such as *KISS1*. The loss of [MKRN3](/details-gene/7681) would relieve this translational repression, contributing to precocious puberty. 3. The significant expression of [MKRN3](/details-gene/7681) in [monocyte](/details-cell/CL0000576)s implies an uncharacterized role in innate immunity. [MKRN3](/details-gene/7681) may ubiquitinate key signaling adaptors in inflammatory pathways, thereby modulating cytokine production or monocyte differentiation. **Suggested Experimental Approach:** To test the first hypothesis and identify the direct protein substrates of [MKRN3](/details-gene/7681) in a physiologically relevant context, an unbiased proteomics approach could be employed. Specifically, a hypothalamic neuronal cell line could be engineered to express a tagged version of [MKRN3](/details-gene/7681). Co-immunoprecipitation of the tagged [MKRN3](/details-gene/7681) followed by mass spectrometry (IP-MS) would identify interacting proteins. To pinpoint direct ubiquitination targets, this could be coupled with ubiquitin remnant profiling (di-Gly proteomics), comparing wild-type cells to [MKRN3](/details-gene/7681) knockout cells to identify proteins whose ubiquitination status is dependent on [MKRN3](/details-gene/7681) activity. **Therapeutic Potential:** Given that central precocious puberty is caused by a loss of [MKRN3](/details-gene/7681) function, the therapeutic goal would be to restore or mimic its inhibitory activity rather than to inhibit it. This makes [MKRN3](/details-gene/7681) a challenging drug target. Directly activating a specific E3 ligase is pharmacologically difficult. However, identifying its key downstream targets could reveal more druggable nodes. For instance, if [MKRN3](/details-gene/7681) is found to degrade a specific puberty-activating kinase or receptor, developing a small molecule inhibitor for that downstream target could offer a viable therapeutic strategy for treating [MKRN3](/details-gene/7681)-deficient precocious puberty.

Genular Protein ID: 1206691578

Symbol: MKRN3_HUMAN

Name: Probable E3 ubiquitin-protein ligase makorin-3

UniProtKB Accession Codes:

Q13064

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 2 EMBL 2 Ensembl 1 ExpressionAtlas 1 GO 7 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 MoonDB 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PIR 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 SIGNOR 1 SMART 2 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 UniProtKB 2 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10196367

Title: A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.

PubMed ID: 10196367

DOI: 10.1093/hmg/8.5.783

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 19066619

Title: A paternal deletion of MKRN3, MAGEL2 and NDN does not result in Prader-Willi syndrome.

PubMed ID: 19066619

DOI: 10.1038/ejhg.2008.232

PubMed ID: 16959974

Title: The consensus coding sequences of human breast and colorectal cancers.

PubMed ID: 16959974

DOI: 10.1126/science.1133427

PubMed ID: 23738509

Title: Central precocious puberty caused by mutations in the imprinted gene MKRN3.

PubMed ID: 23738509

DOI: 10.1056/nejmoa1302160

PubMed ID: 25011910

Title: MKRN3 mutations in familial central precocious puberty.

PubMed ID: 25011910

DOI: 10.1159/000362815

PubMed ID: 25316453

Title: A novel MKRN3 missense mutation causing familial precocious puberty.

PubMed ID: 25316453

DOI: 10.1093/humrep/deu256

PubMed ID: 24438377

Title: Central precocious puberty in a girl and early puberty in her brother caused by a novel mutation in the MKRN3 gene.

PubMed ID: 24438377

DOI: 10.1210/jc.2013-4084

PubMed ID: 24628548

Title: Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3.

PubMed ID: 24628548

DOI: 10.1210/jc.2013-3126

Sequence Information:

  • Length: 507
  • Mass: 55645
  • Checksum: 2EDBA91190F3A292
  • Sequence:
    • MEEPAAPSEA HEAAGAQAGA EAAREGVSGP DLPVCEPSGE SAAPDSALPH AARGWAPFPV 
APVPAHLRRG GLRPAPASGG GAWPSPLPSR SSGIWTKQII CRYYIHGQCK EGENCRYSHD 
LSGRKMATEG GVSPPGASAG GGPSTAAHIE PPTQEVAEAP PAASSLSLPV IGSAAERGFF 
EAERDNADRG AAGGAGVESW ADAIEFVPGQ PYRGRWVASA PEAPLQSSET ERKQMAVGSG 
LRFCYYASRG VCFRGESCMY LHGDICDMCG LQTLHPMDAA QREEHMRACI EAHEKDMELS 
FAVQRGMDKV CGICMEVVYE KANPNDRRFG ILSNCNHSFC IRCIRRWRSA RQFENRIVKS 
CPQCRVTSEL VIPSEFWVEE EEEKQKLIQQ YKEAMSNKAC RYFAEGRGNC PFGDTCFYKH 
EYPEGWGDEP PGPGGGSFSA YWHQLVEPVR MGEGNMLYKS IKKELVVLRL ASLLFKRFLS 
LRDELPFSED QWDLLHYELE EYFNLIL