MKRN3

Summary

MKRN3 (makorin ring finger protein 3, HGNC:7114) is a protein-coding gene on chromosome 15q11.2, encoding E3 ubiquitin-protein ligase makorin-3 (Q13064). E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins.

The protein encoded by this gene contains a RING (C3HC4) zinc finger motif and several C3H zinc finger motifs. This gene is intronless and imprinted, with expression only from the paternal allele. Disruption of the imprinting at this locus may contribute to Prader-Willi syndrome. An antisense RNA of unknown function has been found overlapping this gene.

Source: NCBI Gene 7681 — RefSeq curated summary.

At a glance

• Gene–disease (curated): precocious puberty, central, 2 (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 123 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 99
• Druggable target: yes
• MANE Select transcript: NM_005664

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7114
Approved symbol	MKRN3
Name	makorin ring finger protein 3
Location	15q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RNF63, ZFP127, MGC88288
Ensembl gene	ENSG00000179455
Ensembl biotype	protein_coding
OMIM	603856
Entrez	7681

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000314520, ENST00000564592, ENST00000568252, ENST00000568945, ENST00000570112, ENST00000647595, ENST00000649065, ENST00000676568, ENST00000677119, ENST00000677372, ENST00000678440, ENST00000679144

RefSeq mRNA: 1 — MANE Select: NM_005664 NM_005664

CCDS: CCDS10013

Canonical transcript exons

ENST00000314520 — 1 exons

Exon	Start	End
ENSE00001272708	23565674	23568044

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 83.95.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1463 / max 133.9026, expressed in 593 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145470	1.7960	570
145471	0.1008	49
145473	0.0914	36
207433	0.0782	24
145474	0.0376	7
145475	0.0235	6
145476	0.0126	3
145472	0.0060	3

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	83.95	gold quality
cortical plate	UBERON:0005343	82.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.45	gold quality
ventricular zone	UBERON:0003053	80.14	gold quality
lower esophagus mucosa	UBERON:0035834	79.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.38	gold quality
spinal cord	UBERON:0002240	76.44	gold quality
corpus callosum	UBERON:0002336	76.11	gold quality
buccal mucosa cell	CL:0002336	74.17	gold quality
amygdala	UBERON:0001876	72.28	gold quality
minor salivary gland	UBERON:0001830	70.95	gold quality
esophagus mucosa	UBERON:0002469	70.78	gold quality
embryo	UBERON:0000922	70.27	gold quality
putamen	UBERON:0001874	69.83	gold quality
prefrontal cortex	UBERON:0000451	69.58	gold quality
caudate nucleus	UBERON:0001873	69.49	gold quality
nucleus accumbens	UBERON:0001882	69.21	gold quality
saliva-secreting gland	UBERON:0001044	69.13	gold quality
mouth mucosa	UBERON:0003729	68.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.71	gold quality
substantia nigra	UBERON:0002038	68.56	gold quality
Ammon’s horn	UBERON:0001954	68.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	68.06	gold quality
midbrain	UBERON:0001891	67.89	gold quality
right uterine tube	UBERON:0001302	67.11	gold quality
cingulate cortex	UBERON:0003027	67.05	gold quality
anterior cingulate cortex	UBERON:0009835	66.79	gold quality
telencephalon	UBERON:0001893	66.70	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	66.23	gold quality
neocortex	UBERON:0001950	66.21	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting MKRN3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4779	99.86	66.50	1583

Literature-anchored findings (GeneRIF, showing 40)

• MKRN3 gene is imprinted, with preferential expression from the paternal allele. (PMID:10196367)
• Deficiency of MKRN3 causes central precocious puberty in humans. (PMID:23738509)
• A novel MKRN3 mutation (p.C340G) in a girl with central precocious puberty and her brother with early puberty. (PMID:24438377)
• this study identified novel inherited MKRN3 defects in children with apparently sporadic central precocious puberty, supporting a fundamental role of this peptide in the suppression of the reproductive axis. (PMID:24628548)
• MKRN3 mutations appear to be a frequent cause of familial CPP and, considering the imprinted mode of inheritance, may also account for a certain proportion of isolated CPP cases. (PMID:25011910)
• The MKRN3 protein has a fundamental role in determining pubertal timing. (PMID:25316453)
• Declining levels of circulating MKRN3 preceded pubertal onset. The negative correlation between MKRN3 and gonadotropins further supports MKRN3 as a major regulator of hypothalamic GnRH secretion during childhood. (PMID:25695892)
• the present study reveals a relatively low number of MKRN 3 mutations in Korean girls with CPP. (PMID:25938887)
• MKRN3 plays an inhibitory role in the reproductive axis to represent a new pathway in pubertal regulation. [Review] (PMID:25957321)
• Data indicate that a novel mutation in the makorin ring finger protein 3 (MKRN3) gene in two sisters with central precocious puberty (CPP) was identified. (PMID:26173472)
• Data show similar circulating MKRN3 levels in men with congenital hypogonadotropic hypogonadism (CHH)and healthy controls. (PMID:26175221)
• Case Report: MKRN3 missense mutation in a Danish girl with central precocious puberty and her brother with early puberty. (PMID:26331766)
• prevalence of MKNR3 mutations is high in familial cases of idiopathic central precocious puberty (iCPP); onset occurs earlier in patients with MKRN3 mutations than in those without the mutations and sexual dimorphism for age at puberty onset persists in patients with mutations; MKRN3 mutations accelerate postnatal development of the gonadotropic axis (PMID:26431553)
• Peripheral MKRN3 levels in boys appear to serve as a readout of the diminishing central inhibition that controls the onset of puberty. (PMID:27025240)
• Declining MKRN3 before pubertal onset support MKRN3 as an inhibitor of GnRH secretion during midchildhood. (PMID:27057785)
• This study demonstrated a high frequency of MKRN3 mutations in boys with Central Precocious Puberty , previously classified as idiopathic, suggesting the importance of genetic analysis in this group. (PMID:27225315)
• The identification of carriers of MKRN3 mutations may contribute to early diagnosis of Central Precocious Puberty, facilitating treatment decisions and guiding genetic counseling and prompt intervention in familial cases. (PMID:27424312)
• The genetic findings in our patients’ cohort with central precocious puberty are in agreement with the hypothesis that the MKRN3 gene may act as an inhibitor of GnRH secretion during childhood. 13 It seems that MKRN3 gene alterations do not necessarily lead to early pubertal development in males, but paternally inherited MKRN3 mutations are responsible for central precocious puberty in females. (PMID:27640350)
• Two heterozygous frameshift mutations (c.441_441delG, p.H148Tfs*23 and c803_803delAT, p.M268Vfs*23) were described in the MKRN3 gene in 2 probands with familial idiopathic central precocious puberty and in some of their family members. These frameshift mutations create a premature stop codon and result in a truncated protein. (PMID:27798941)
• MKRN3 is the most frequent genetic cause of familial Idiopathic Central Precocious Puberty, so it is wise to screen for MKRN3 mutations in all patients with familial Idiopathic Central Precocious Puberty and in patients with an unclear paternal pubertal history. (PMID:27931036)
• Data suggest that a familial case of CPP (central precocious puberty) in which three out of four girls are affected is due to a novel MKRN3 nonsense mutation (p.Glu298Ter, N/E298); the affected siblings are the proband/oldest sister and the youngest sisters, monozygotic twins; there are no sons in this family; the next-to-oldest sister and the father are carriers of this nonsense mutation. [CASE REPORT; LETTER] (PMID:28132164)
• MKRN3 is involvedt in central precocious puberty also in absence of deleterious mutations, although our sample size is small. Role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition. (PMID:28299573)
• The prevalence of MKRN3 mutations in our cohort of girls with central precocious puberty was similar to that reported in the literature in sporadic cases but lower than previously described in familial ones. (PMID:28672280)
• MKRN3 23566445 C/T polymorphism was associated with precocious puberty. (PMID:28988223)
• This study supports the impact of MKRN3 SNP rs12441827 on precocious puberty in Korean boys. (PMID:30053798)
• MKRN3 DMR was found aberrantly hypermethylated in all control and AS iPSCs, regardless of the methylation status of the PWS-IC master regulator. This suggests a loss of hierarchical control of imprinting at PWS/AS region. (PMID:30102380)
• Girls with central precocious puberty had a decline in peripheral levels of MKRN3 during GnRHa treatment. This suggests a suppression of MKRN3 by continuous pharmacological administration of GnRHa. (PMID:30269125)
• The measurement of serum MKRN3 level may provide some help for Central precocious puberty prediction, but relatively various values need further validation. (PMID:30806524)
• Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog. (PMID:31671431)
• Evaluation of serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty and premature thelarche. (PMID:31852205)
• MKRN3 and KISS1R mutations in precocious and early puberty. (PMID:32228714)
• MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons. (PMID:32407292)
• Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome. (PMID:32480405)
• Familial central precocious puberty: two novel MKRN3 mutations. (PMID:33214675)
• Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations. (PMID:33383582)
• The role of makorin ring finger protein-3, kisspeptin, and neurokinin B in the physiology of minipuberty. (PMID:33675211)
• MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty. (PMID:33744966)
• E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer. (PMID:34143182)
• [Clinical and molecular genetic features of 3 family cases of the central precocious puberty, due to MKRN3 gene defects]. (PMID:34297502)
• The Key Roles of Makorin RING Finger Protein 3 (MKRN3) During the Development of Pubertal Initiation and Central Precocious Puberty (CPP). (PMID:35748557)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	mkrn1	ENSDARG00000041665
mus_musculus	Mkrn3	ENSMUSG00000070527
rattus_norvegicus	Mkrn3	ENSRNOG00000010172
drosophila_melanogaster	Mkrn1	FBGN0029152
drosophila_melanogaster	CG5334	FBGN0030577
drosophila_melanogaster	CG5347	FBGN0030578
drosophila_melanogaster	CG12477	FBGN0036809
caenorhabditis_elegans		WBGENE00002278

Paralogs (3): MKRN2 (ENSG00000075975), MKRN1 (ENSG00000133606), (ENSG00000300293)

Protein

Protein identifiers

E3 ubiquitin-protein ligase makorin-3 — Q13064 (reviewed: Q13064)

Alternative names: RING finger protein 63, RING-type E3 ubiquitin transferase makorin-3, Zinc finger protein 127

All UniProt accessions (11): Q13064, A0A3B3IRN4, A0A3B3IRU9, A0A3B3ISD8, A0A7I2V2Q0, A0A7I2V2S4, A0A7I2V4D6, A0A7I2V6H1, A0A7I2YQ72, H3BPL3, Q6NSB6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Acts as a key developmental timer that helps ensure puberty begins at the appropriate age, by inhibiting premature activation of the reproductive hormone cascade. Epigenetically regulates GNRH1 transcription by disrupting the binding of methyl-DNA binding protein 3/MBD3 to the promoter of GNRH1. Mechanistically, mediates the non-proteolytic ubiquitination of MBD3 at multiple sites with ‘Lys27’ ubiquitin linkages and thereby regulates the methylation status of the genome, including GNRH1 promoter. Modulates the stability and translation of GNRH1 mRNA by mediating the non-proteolytic ubiquitination of PABP family members PABPC1, PABPC3 and PABPC4 at multiple sites. Also participates in the maintenance of genomic and epigenomic stability by regulating the abundance of APEX2 via ‘Lys-48’-linked ubiquitination.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Disease relevance. Precocious puberty, central 2 (CPPB2) [MIM:615346] A condition defined as the development of secondary sexual characteristics in boys and girls at a chronological age that is 2.5 standard deviations below the mean age at onset of puberty in the population. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Imprinted, expressed from the paternal chromosome only. A deficiency of MKRN3 is not sufficient to cause Prader-Willi syndrome (PWS).

RefSeq proteins (1): NP_005655* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR031644	MKRN1_C	Domain
IPR036855	Znf_CCCH_sf	Homologous_superfamily
IPR041367	Znf-CCCH_4	Domain
IPR045072	MKRN-like	Family

Pfam: PF00097, PF14608, PF15815, PF18044

UniProt features (16 total): sequence variant 6, zinc finger region 4, region of interest 4, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9P2Q	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13064-F1	64.59	0.21

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 310 (showing top): HATADA_METHYLATED_IN_LUNG_CANCER_DN, chr15q11, AML_Q6, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, AML1_01, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, CETS1P54_01, E2A_Q2, GOCC_RIBONUCLEOPROTEIN_COMPLEX, MGGAAGTG_GABP_B, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY, GOMF_UBIQUITIN_LIKE_PROTEIN_LIGASE_ACTIVITY

GO Biological Process (2): protein polyubiquitination (GO:0000209), protein ubiquitination (GO:0016567)

GO Molecular Function (7): RNA binding (GO:0003723), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), ribonucleoprotein complex (GO:1990904)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	1
protein modification by small protein conjugation	1
nucleic acid binding	1
transition metal ion binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
protein-containing complex	1

Protein interactions and networks

STRING

666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MKRN3	MAGEL2	Q9UJ55	942
MKRN3	SNRPN	P14648	939
MKRN3	NDN	Q99608	922
MKRN3	ATP10A	O60312	895
MKRN3	SNURF	Q9Y675	817
MKRN3	NPAP1	Q9NZP6	811
MKRN3	UBE3A	P78355	805
MKRN3	OCA2	Q04671	798
MKRN3	GABRB3	P28472	746
MKRN3	GNRH1	P01148	739
MKRN3	KISS1	Q15726	696
MKRN3	KISS1R	Q969F8	678
MKRN3	TUBGCP5	Q96RT8	623
MKRN3	IGFBP2	P18065	594
MKRN3	DLK1	P15803	583

IntAct

571 interactions, top by confidence:

A	B	Type	Score
MKRN3	PRPF31	psi-mi:“MI:0915”(physical association)	0.860
PRPF31	MKRN3	psi-mi:“MI:0915”(physical association)	0.860
MKRN3	MDM4	psi-mi:“MI:0915”(physical association)	0.790
MDM4	MKRN3	psi-mi:“MI:0915”(physical association)	0.790
MKRN3	TCHP	psi-mi:“MI:0915”(physical association)	0.780
TCHP	MKRN3	psi-mi:“MI:0915”(physical association)	0.780
MKRN3	MKRN3	psi-mi:“MI:0915”(physical association)	0.740
PSMA1	MKRN3	psi-mi:“MI:0915”(physical association)	0.720
MKRN3	FAM110A	psi-mi:“MI:0915”(physical association)	0.720
MKRN3	SCNM1	psi-mi:“MI:0915”(physical association)	0.720
BEX2	MKRN3	psi-mi:“MI:0915”(physical association)	0.720
SCNM1	MKRN3	psi-mi:“MI:0915”(physical association)	0.720
MKRN3	BEX2	psi-mi:“MI:0915”(physical association)	0.720
FAM110A	MKRN3	psi-mi:“MI:0915”(physical association)	0.720
POLR1C	MKRN3	psi-mi:“MI:0915”(physical association)	0.700
TLE5	MKRN3	psi-mi:“MI:0915”(physical association)	0.700
MKRN3	POLR1C	psi-mi:“MI:0915”(physical association)	0.700

BioGRID (257): MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), MKRN3 (Two-hybrid), FARS2 (Two-hybrid), PRPF31 (Two-hybrid), RBM41 (Two-hybrid), NABP1 (Two-hybrid), MRPS6 (Two-hybrid)

ESM2 similar proteins: A0A0N7KMH0, A2PZN8, A2WY46, A2X7Q3, A2XKR7, A2Y007, A3BH91, B6SM63, B8AMA9, B8AR30, B8B0I8, B8B8I3, B8B8J2, B8BF91, C0HBT3, F4I7L1, O65001, Q01JG2, Q0DNU1, Q0E0A6, Q0JBF0, Q0JGS5, Q0JJ01, Q10F25, Q13064, Q17RB8, Q2QM17, Q2QYL8, Q2RBE3, Q60764, Q657C0, Q67TP9, Q6EPZ0, Q6EPZ2, Q6H668, Q6IEK5, Q75LH6, Q75LX7, Q75LX9, Q7GDL5

Diamond homologs: A0A7H0DMZ7, B0F0H3, E0X9N4, P0C775, P17366, P87607, Q13064, Q13434, Q49PZ0, Q4SRI6, Q4VBT5, Q5NU13, Q5NU14, Q5ZA07, Q60764, Q6GLD9, Q6GLT5, Q6IDS6, Q76R05, Q805K3, Q85318, Q8JFF3, Q8QN38, Q8V571, Q9DD48, Q9DFG8, Q9ERV1, Q9H000, Q9N373, Q9QXP6, Q9TT91, Q9UHC7, B6VQ60, P0CS64, P0CS65, Q6NVV0, Q9M022, A9LNK9, O19137, O95639

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	MKRN3	ubiquitination
MKRN3	“down-regulates activity”	PABPC1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

123 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	68
Likely benign	30
Benign	6

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
2431610	NM_005664.4(MKRN3):c.482del (p.Pro161fs)	Pathogenic
3900268	NM_005664.4(MKRN3):c.862del (p.Ala288fs)	Pathogenic
438339	NM_005664.4(MKRN3):c.982C>T (p.Arg328Cys)	Pathogenic
56901	NM_005664.4(MKRN3):c.637del (p.Arg213fs)	Pathogenic
56902	NM_005664.4(MKRN3):c.1172dup (p.Tyr391Ter)	Pathogenic
56903	NM_005664.4(MKRN3):c.1095G>T (p.Arg365Ser)	Pathogenic
1189862	NM_005664.4(MKRN3):c.802_803del (p.Met268fs)	Likely pathogenic
3779852	NM_005664.4(MKRN3):c.137C>A (p.Ser46Ter)	Likely pathogenic
523975	NM_005664.4(MKRN3):c.694_695del (p.Arg232fs)	Likely pathogenic
625144	NM_005664.4(MKRN3):c.326G>A (p.Cys109Tyr)	Likely pathogenic
817441	NM_005664.4(MKRN3):c.208_214dup (p.Leu72fs)	Likely pathogenic

SpliceAI

125 predictions. Top by Δscore:

Variant	Effect	Δscore
15:23566805:TAGG:T	acceptor_gain	0.7000
15:23566505:G:GA	acceptor_gain	0.5900
15:23566528:GGGGA:G	acceptor_gain	0.5900
15:23565835:C:T	donor_gain	0.5700
15:23566806:AGGTG:A	acceptor_gain	0.5500
15:23565839:TGCTG:T	donor_gain	0.5400
15:23566804:TTAGG:T	acceptor_gain	0.5400
15:23566371:GT:G	donor_gain	0.4900
15:23565838:GTGC:G	donor_gain	0.4600
15:23565840:GCTG:G	donor_gain	0.4600
15:23566803:A:T	acceptor_gain	0.4200
15:23566370:TGTAG:T	donor_gain	0.4100
15:23566478:G:GT	donor_gain	0.4100
15:23566529:GGGAG:G	acceptor_gain	0.4000
15:23566807:G:T	acceptor_gain	0.4000
15:23566807:GGT:G	acceptor_gain	0.4000
15:23566807:GGTGT:G	acceptor_gain	0.3700
15:23566245:G:GT	donor_gain	0.3600
15:23565770:TGCCA:T	donor_gain	0.3300
15:23566501:G:A	acceptor_gain	0.3300
15:23566527:AG:A	acceptor_gain	0.3300
15:23566528:GG:G	acceptor_gain	0.3300
15:23566705:ACAAG:A	donor_loss	0.3300
15:23566706:CAAG:C	donor_loss	0.3300
15:23566707:AAG:A	donor_loss	0.3300
15:23566708:AG:A	donor_loss	0.3300
15:23566709:GGTG:G	donor_loss	0.3300
15:23566710:G:GA	donor_loss	0.3300
15:23566711:T:C	donor_loss	0.3300
15:23566669:A:G	donor_loss	0.3200

AlphaMissense

3324 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:23566767:T:C	F329L	0.999
15:23566769:T:A	F329L	0.999
15:23566769:T:G	F329L	0.999
15:23566793:T:A	H337Q	0.998
15:23566793:T:G	H337Q	0.998
15:23566797:T:C	F339L	0.998
15:23566799:C:A	F339L	0.998
15:23566799:C:G	F339L	0.998
15:23566823:G:C	W347C	0.998
15:23566823:G:T	W347C	0.998
15:23566825:G:C	R348T	0.998
15:23566863:T:C	C361R	0.998
15:23566821:T:A	W347R	0.997
15:23566821:T:C	W347R	0.997
15:23566826:A:C	R348S	0.997
15:23566826:A:T	R348S	0.997
15:23566872:T:A	C364S	0.997
15:23566872:T:C	C364R	0.997
15:23566873:G:C	C364S	0.997
15:23566989:T:C	F403L	0.997
15:23566991:T:A	F403L	0.997
15:23566991:T:G	F403L	0.997
15:23567010:T:A	C410S	0.997
15:23567010:T:C	C410R	0.997
15:23567011:G:C	C410S	0.997
15:23567016:T:C	F412L	0.997
15:23567018:T:A	F412L	0.997
15:23567018:T:G	F412L	0.997
15:23566768:T:C	F329S	0.996
15:23566786:G:A	C335Y	0.996

dbSNP variants (sampled 300 via entrez): RS1000780930 (15:23566385 G>A,C), RS1000983092 (15:23565545 C>A,G,T), RS1001246877 (15:23565351 T>TA), RS1002498190 (15:23565176 A>C,G), RS1002930101 (15:23567917 AATAT>A,AAT,AATATAT), RS1004369260 (15:23566215 A>G), RS1004444369 (15:23567193 G>A,T), RS1004774700 (15:23567418 T>A,G), RS1005371940 (15:23566173 G>A), RS1007021015 (15:23565681 C>A,T), RS1007620178 (15:23564466 G>T), RS1008453301 (15:23565614 A>C), RS1009533218 (15:23566878 G>A), RS1009942883 (15:23565621 A>C,G,T), RS1010605011 (15:23566827 A>G,T)

Disease associations

OMIM: gene MIM:603856 | disease phenotypes: MIM:615346, MIM:176270

GenCC curated gene-disease

Disease	Classification	Inheritance
precocious puberty, central, 2	Strong	Autosomal dominant

Mondo (2): precocious puberty, central, 2 (MONDO:0014137), Prader-Willi syndrome (MONDO:0008300)

Orphanet (2): NON RARE IN EUROPE: Central precocious puberty (Orphanet:759), Prader-Willi syndrome (Orphanet:739)

HPO phenotypes

99 total (30 of 99 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000060	Clitoral hypoplasia
HP:0000064	Hypoplastic labia minora
HP:0000219	Thin upper lip vermilion
HP:0000268	Dolichocephaly
HP:0000341	Narrow forehead
HP:0000446	Narrow nasal bridge
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000670	Carious teeth
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000717	Autism
HP:0000750	Delayed speech and language development
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000826	Precocious puberty
HP:0000842	Hyperinsulinemia
HP:0000846	Adrenal insufficiency
HP:0000876	Oligomenorrhea
HP:0000938	Osteopenia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002541_101	Menarche (age at onset)	5.000000e-11
GCST008758_92	Pre-treatment viral load in HIV-1 infection	1.000000e-15
GCST008839_197	Height	6.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0010125	viral load

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011218	Prader-Willi Syndrome	C10.597.606.360.690; C16.131.077.730; C16.131.260.700; C16.320.180.700; C16.320.447.500; C18.654.726.750.500.740

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067102 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Thimerosal	decreases expression	1
Urethane	affects expression	1
Sodium Selenite	decreases expression	1
Citric Acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651795	Binding	Binding affinity to human MKRN3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7V5	Ubigene A-549 MKRN3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

135 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01298180	PHASE4	COMPLETED	Is There a Sensibility Increased in the Growth Hormone at Child With Prader-Willi Syndrome?
NCT01542242	PHASE4	TERMINATED	Liraglutide Use in Prader-Willi Syndrome
NCT03031626	PHASE4	COMPLETED	Oxygen Versus Medical Air for Treatment of CSA in Prader Will Syndrome
NCT03616509	PHASE4	COMPLETED	GH in Adults With PWS, Effect on Hypotonia Evaluated by Functional MRI, Relationship With Strength and Body Composition
NCT04066088	PHASE4	WITHDRAWN	Dose Clinical Trial of Guanfacine Extended Release for the Reduction of Aggression and Self-injuries Behavior Associated With Prader-Willi Syndrome
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06901245	PHASE4	RECRUITING	Tirzepatide in PWS, HO and GNSO
NCT00175305	PHASE3	TERMINATED	Prader-Willi Syndrome and Appetite
NCT00444964	PHASE3	COMPLETED	Growth Hormone Use in Adults With Prader-Willi Syndrome
NCT00603109	PHASE3	TERMINATED	Effect of Rimonabant on Weight Gain and Body Composition in Adults With Prader Willi Syndrome
NCT02179151	PHASE3	TERMINATED	Double-Blind, Placebo Controlled, Phase 3 Trial of ZGN-440 (Beloranib) in Obese Subjects With Prader-Willi Syndrome
NCT02204163	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Eutropin in Prader-Willi Syndrome
NCT02810483	PHASE3	TERMINATED	Study of the Efficacy of Topiramate in Patients With Prader Willi Syndrome Over 8 Weeks
NCT03440814	PHASE3	COMPLETED	A Study of Diazoxide Choline in Patients With Prader-Willi Syndrome
NCT03554031	PHASE3	UNKNOWN	A Study to Evaluate the Efficacy and Safety of Recombinant Human Growth Hormone Injection in Patients With Prader-Willi Syndrome
NCT03649477	PHASE3	COMPLETED	Phase 3 Study of Intranasal Carbetocin (LV-101) in Patients With Prader-Willi Syndrome
NCT03714373	PHASE3	COMPLETED	Open-Label Extension Study of DCCR in PWS Followed by Double-Blind, Placebo-Controlled, Randomized Withdrawal Period
NCT04086810	PHASE3	WITHDRAWN	An Open-Label Study of DCCR Tablet in Patients With PWS
NCT04283578	PHASE3	COMPLETED	Oxytocin Treatment in Neonates and Infants With Prader-Willi Syndrome
NCT04697381	PHASE3	COMPLETED	Study of the Efficacy and Safety of Somatropin in Japanese Participants With PWS
NCT05032326	PHASE3	UNKNOWN	Long-term Interventional Follow-up Study of Children With Prader-Willi Syndrome Included in the OTBB3 Clinical Trial
NCT05387798	PHASE3	WITHDRAWN	A Phase 3 Extension Study of RAD011 (Cannabidiol Oral Solution) in Patients With Prader-Willi Syndrome
NCT05701774	PHASE3	ACTIVE_NOT_RECRUITING	Open-Label Extension Study of DCCR in Patients With Prader-Willi Syndrome
NCT06144645	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Evaluation of Non-Invasive Vagus Nerve Stimulation for Temper Outbursts in People With PWS
NCT06366464	PHASE3	RECRUITING	A Study of Pitolisant in Patients With Prader-Willi Syndrome
NCT06828861	PHASE3	SUSPENDED	ARD-101 for Treatment of PWS: The Hunger Elimination or Reduction Objective Trial
NCT07197034	PHASE3	SUSPENDED	The Hunger Elimination or Reduction Objective (HERO ) Open -Label Extension (OLE) Trial
NCT07219485	PHASE3	ENROLLING_BY_INVITATION	A Study of Pitolisant in Participants With Prader-Willi Syndrome
NCT01038570	PHASE2	COMPLETED	Comparative Study Between Prader-Willi Patients Who Take Oxytocin Versus Placebo
NCT01818921	PHASE2	COMPLETED	An Efficacy, Safety, and Pharmacokinetics Study of Beloranib in Obese Subjects With Prader-Willi Syndrome
NCT02311673	PHASE2	COMPLETED	Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome
NCT02629991	PHASE2	COMPLETED	Oxytocin vs. Placebo for the Treatment Hyperphagia in Children and Adolescents With Prader-Willi Syndrome
NCT02844933	PHASE2	TERMINATED	Cannabidiol Oral Solution for the Treatment of Patients With Prader-Willi Syndrome
NCT02893618	PHASE2	UNKNOWN	A 5 Treatment Period Pharmacokinetic Study Evaluating Dose Proportionality and Food Effects of Diazoxide Choline Controlled-Release Tablet (DCCR)
NCT03197662	PHASE2	COMPLETED	Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome
NCT03274856	PHASE2	COMPLETED	A Study of GLWL-01 in Patients With Prader-Willi Syndrome
NCT03458416	PHASE2	TERMINATED	A Study to Assess the Long-Term Safety of Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Participants With Prader-Willi Syndrome
NCT03831425	PHASE2	WITHDRAWN	Mitochondrial Complex I Dysfunction in PWS
NCT03848481	PHASE2	TERMINATED	CBDV vs Placebo in Children and Adults up to Age 30 With Prader-Willi Syndrome (PWS)
NCT04257929	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Safety and Efficacy of Pitolisant in Patients With Prader-Willi Syndrome, Followed by an Open Label Extension