MLN

Summary

MLN (motilin, HGNC:7141) is a protein-coding gene on chromosome 6p21.31, encoding Promotilin (P12872). Plays an important role in the regulation of interdigestive gastrointestinal motility and indirectly causes rhythmic contraction of duodenal and colonic smooth muscle.

This gene encodes a small peptide hormone that is secreted by cells of the small intestine to regulate gastrointestinal contractions and motility. Proteolytic processing of the secreted protein produces the mature peptide and a byproduct referred to as motilin-associated peptide (MAP). Three transcript variants encoding different preproprotein isoforms but the same mature peptide have been found for this gene.

Source: NCBI Gene 4295 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 19 total
• Druggable target: yes
• MANE Select transcript: NM_002418

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7141
Approved symbol	MLN
Name	motilin
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000096395
Ensembl biotype	protein_coding
OMIM	158270
Entrez	4295

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000266003, ENST00000430124, ENST00000507738, ENST00000960632

RefSeq mRNA: 3 — MANE Select: NM_002418 NM_001040109, NM_001184698, NM_002418

CCDS: CCDS47412, CCDS4786, CCDS54993

Canonical transcript exons

ENST00000430124 — 5 exons

Exon	Start	End
ENSE00000738724	33799105	33799221
ENSE00000849455	33795503	33795605
ENSE00000849456	33801047	33801170
ENSE00001675754	33794673	33794835
ENSE00001817221	33803953	33804003

Expression profiles

Bgee: expression breadth ubiquitous, 116 present calls, max score 92.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2453 / max 128.0077, expressed in 19 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73192	0.2453	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	92.54	gold quality
jejunal mucosa	UBERON:0000399	82.85	gold quality
jejunum	UBERON:0002115	76.34	gold quality
cervix squamous epithelium	UBERON:0006922	71.76	gold quality
diaphragm	UBERON:0001103	71.09	gold quality
endometrium epithelium	UBERON:0004811	71.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.58	gold quality
frontal pole	UBERON:0002795	69.54	gold quality
middle frontal gyrus	UBERON:0002702	69.18	gold quality
paraflocculus	UBERON:0005351	69.13	gold quality
tongue squamous epithelium	UBERON:0006919	68.83	gold quality
epithelial cell of pancreas	CL:0000083	68.30	gold quality
thymus	UBERON:0002370	68.17	gold quality
oocyte	CL:0000023	67.87	gold quality
olfactory bulb	UBERON:0002264	67.20	gold quality
secondary oocyte	CL:0000655	67.12	gold quality
cerebellar vermis	UBERON:0004720	66.52	gold quality
cervix epithelium	UBERON:0004801	65.26	gold quality
Brodmann (1909) area 10	UBERON:0013541	65.01	gold quality
trachea	UBERON:0003126	64.73	gold quality
orbitofrontal cortex	UBERON:0004167	64.35	gold quality
type B pancreatic cell	CL:0000169	63.13	gold quality
pancreatic ductal cell	CL:0002079	63.01	silver quality
nipple	UBERON:0002030	62.69	gold quality
dorsal plus ventral thalamus	UBERON:0001897	62.34	gold quality
pericardium	UBERON:0002407	62.13	gold quality
cardia of stomach	UBERON:0001162	62.10	gold quality
dorsal root ganglion	UBERON:0000044	62.04	gold quality
upper arm skin	UBERON:0004263	62.04	gold quality
pharyngeal mucosa	UBERON:0000355	61.72	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting MLN, 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-1251-3P	99.64	67.21	1408
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6774-5P	95.94	65.18	722

Literature-anchored findings (GeneRIF, showing 12)

• Plasma levels of motilin were studied in 16 untreated Celiac disease patients and in an age-matched control group of 18 healthy subjects by radioimmunoassay and by high-performance liquid chromatography (HPLC). (PMID:12732349)
• Ghrelin and motilin are cosecreted from a prominent endocrine cell population in the small intestine. (PMID:17595255)
• The abnormal excretion of hormonal factors is closely related to gallstone formation (PMID:18234640)
• About 35.9% of the patients with a T tube after cholecystectomy and choledochotomy have duodenal-biliary reflux. Most of them have sphincter of Oddi hypomotility and the decreased level of plasma motilin and serum gastrin. (PMID:18609694)
• Ghrelin covaried with motilin in plasma in irritable bowel syndrome (IBS) but not in plasma from healthy subjects. This suggests the two peptides act together in IBS. (PMID:20338210)
• Motilin may directly influence adipocyte functions by stimulating energy storage. (PMID:21771971)
• Motilin stimulates growth hormone secretion and regulates interdigestive migrating contractions and fasting motor patterns in the gastrointestinal tract. [REVIEW] (PMID:22632857)
• motilin-induced phase III contractions signal hunger in healthy subjects and that this system is disturbed in morbidly obese patients–{REVIEW} (PMID:26660537)
• Serum motilin levels and motilin gene polymorphisms in children with functional constipation. (PMID:27706119)
• Hemodialysis improves upper GI symptoms and gastric slow waves in CKD patients. An increase in ghrelin and a decrease in GLP-1 might be involved in the HD-induced improvement in gastric slow waves. (PMID:28566304)
• Physiological functions and potential clinical applications of motilin. (PMID:36436612)
• Serotonin, ghrelin, and motilin gene/receptor/transporter polymorphisms in childhood functional constipation. (PMID:36888769)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Promotilin — P12872 (reviewed: P12872)

All UniProt accessions (1): P12872

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of interdigestive gastrointestinal motility and indirectly causes rhythmic contraction of duodenal and colonic smooth muscle.

Subcellular location. Secreted.

Similarity. Belongs to the motilin family.

Isoforms (3)

UniProt ID	Names	Canonical?
P12872-1	1	yes
P12872-2	2
P12872-3	3

RefSeq proteins (3): NP_001035198, NP_001171627, NP_002409* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006737	Motilin_assoc	Domain
IPR006738	Motilin_ghrelin	Domain
IPR015662	Promotilin	Family

Pfam: PF04643, PF04644

UniProt features (9 total): peptide 2, splice variant 2, signal peptide 1, chain 1, region of interest 1, sequence variant 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8IBV	ELECTRON MICROSCOPY	3.19
1LBJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12872-F1	68.67	0.08

Antibody-complex structures (SAbDab): 1 — 8IBV

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-375276	Peptide ligand-binding receptors
R-HSA-416476	G alpha (q) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 53 (showing top): MORF_ATRX, MORF_ESR1, BROWNE_HCMV_INFECTION_48HR_DN, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, MORF_ETV3, AACTTT_UNKNOWN, MYB_Q3, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOMF_SIGNALING_RECEPTOR_BINDING, MORF_MT4, GCM_LTK, MYB_Q5_01, MORF_MYC, GOMF_HORMONE_ACTIVITY, MORF_PAX7

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (3): hormone activity (GO:0005179), motilin receptor binding (GO:0031788), protein binding (GO:0005515)

GO Cellular Component (1): extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by GPCR	2
Class A/1 (Rhodopsin-like receptors)	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
G protein-coupled receptor binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLN	MLNR	O43193	994
MLN	GAST	P01350	888
MLN	NTS	P30990	879
MLN	GHSR	Q92847	866
MLN	PPY	P01298	854
MLN	CCK	P06307	842
MLN	GPR39	O43194	832
MLN	SST	P01166	827
MLN	GHRL	Q9UBU3	827
MLN	SCT	P09683	821
MLN	VIP	P01282	810
MLN	GRP	P07491	758
MLN	PYY	P10082	737
MLN	GIP	P09681	722
MLN	GCG	P01275	722

IntAct

7 interactions, top by confidence:

A	B	Type	Score
MLN	TTC19	psi-mi:“MI:0915”(physical association)	0.560
MLN	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TTC19	MLN	psi-mi:“MI:0915”(physical association)	0.000
MLN	TMX2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (2): MLN (Two-hybrid), TMX2 (Two-hybrid)

ESM2 similar proteins: A0A0D1E6R6, A0A0D1EAR7, A0A172M476, A3F7X2, B6KEU8, D0P1A8, D5KXG9, E7A1Q4, G5EHI7, O39830, P01546, P06498, P06849, P0CU86, P12350, P12872, P13841, P23227, P23705, P33884, P33885, P58806, Q03561, Q04684, Q04685, Q08552, Q0A2G3, Q0A3Q7, Q0Q4F1, Q3V0X1, Q64903, Q64904, Q64905, Q64912, Q64914, Q64917, Q64919, Q67169, Q67180, Q67200

Diamond homologs: O18811, O18845, O46617, O62820, P01307, P12872, P27114, Q99MP5, Q9XSE2, P19863, Q9PRP6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MLN	up-regulates	MLNR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

749 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:33801086:G:C	F26L	0.937
6:33801086:G:T	F26L	0.937
6:33801088:A:G	F26L	0.937
6:33801074:G:C	F30L	0.924
6:33801074:G:T	F30L	0.924
6:33801076:A:G	F30L	0.924
6:33801078:A:G	I29T	0.773
6:33801084:A:T	V27D	0.732
6:33801072:G:A	T31I	0.728
6:33801078:A:T	I29N	0.699
6:33801105:G:T	A20D	0.683
6:33801075:A:G	F30S	0.681
6:33801075:A:C	F30C	0.674
6:33801117:G:T	A16D	0.673
6:33799211:C:G	R43P	0.664
6:33801078:A:C	I29S	0.663
6:33799195:C:A	K48N	0.659
6:33799195:C:G	K48N	0.659
6:33801087:A:C	F26C	0.651
6:33801063:T:A	E34V	0.637
6:33801126:A:T	V13E	0.626
6:33801081:G:T	P28H	0.620
6:33801060:A:G	L35P	0.613
6:33801081:G:C	P28R	0.610
6:33801141:G:T	A8D	0.609
6:33801149:C:A	K5N	0.605
6:33801149:C:G	K5N	0.605
6:33801129:A:T	V12E	0.603
6:33801047:C:A	Q39H	0.589
6:33801047:C:G	Q39H	0.589

dbSNP variants (sampled 300 via entrez): RS1000398265 (6:33795890 A>G,T), RS1000814253 (6:33800278 G>C), RS1001120703 (6:33799917 T>A), RS1001791026 (6:33801690 G>A), RS1001838266 (6:33799024 T>C,G), RS1001893040 (6:33795068 G>A,C,T), RS1002017109 (6:33805097 T>C), RS1002071548 (6:33801976 G>A), RS1002530103 (6:33796236 G>T), RS1002671002 (6:33800213 T>C), RS1002672881 (6:33802797 G>A), RS1003198961 (6:33799960 T>C), RS1003563549 (6:33797882 A>G), RS1003797383 (6:33798448 G>A,T), RS1004081539 (6:33803993 G>T)

Disease associations

OMIM: gene MIM:158270 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5214853 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

35 measured of 36 human assays (36 total across all organisms); most potent 35 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
MOTILIN	KI	0.16 nM
NSC_0	KI	0.447 nM
[leu13]pMOT(1-19)	KI	0.98 nM
[leu13]pMOT(1-22)	KI	1 nM
[ala3,leu13]pMOT(1-14)	KI	1.32 nM
[leu13]pMOT(1-16)	KI	2.14 nM
CAS_52906-92-0	KI	2.3 nM
[leu13]pMOT(1-14)	KI	3.16 nM
[ala11,leu13]pMOT(1-14)	KI	4.57 nM
[ala10,leu13]pMOT(1-14)	KI	5.01 nM
N-ethyl, N-methyl Erythromycin-A enol ether	KI	6.03 nM
[ala12,leu13]pMOT(1-14)	KI	6.31 nM
[ala14,leu13]pMOT(1-14)	KI	7.08 nM
[ala13,leu13]pMOT(1-14)	KI	7.24 nM
Erythromycin-B enol ether	KI	7.59 nM
Erythromycin-A enol ether	KI	19.1 nM
[ala5,leu13]pMOT(1-14)	KI	28.8 nM
[ala8,leu13]pMOT(1-14)	KI	36.3 nM
[ala6,leu13]pMOT(1-14)	KI	46.8 nM
[L-Bpa5,Ile13]Motilin	KI	50 nM
ABT-229	KI	58.9 nM
[ala9,leu13]pMOT(1-14)	KI	75.9 nM
[leu13]pMOT(1-11)	KI	89.1 nM
Erythromycin-B	KI	145 nM
N-ethyl, N-Methyl Erythromycin-A	KI	240 nM
EM-B enolether	KI	324 nM
[D-Bpa5,Ile13]Motilin	KI	420 nM
Erythromycin A Enol Ether	KI	537 nM
(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-6-{[(2R,3S,4R,6S)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-14-ethyl-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-1-oxacyclotetradecane-2,10-dione	KI	1290 nM
[ala7,leu13]pMOT(1-14)	KI	1450 nM
[ala4,leu13]pMOT(1-14)	KI	2570 nM
CAS_114-07-8	KI	3090 nM
[leu13]pMOT(1-9)	KI	4070 nM
[leu13]pMOT(1-7)	KI	6920 nM
[leu13]pMOT(1-5)	KI	8910 nM

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.14	Ki	7200	nM	CHEMBL4789678

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
Carbamazepine	affects response to substance	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	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
CHEMBL5214700	Binding	Selectivity interaction (Enzyme panel (ion channels, GPCRs, other targets)) EUB0000196bCl MLN	Selectivity Literature for EUbOPEN Chemogenomics Library wave 3

Clinical trials (associated diseases)

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