MRLN

Summary

MRLN (myoregulin, HGNC:48649) is a protein-coding gene on chromosome 10q21.2, encoding Myoregulin (P0DMT0). Inhibits the activity of ATP2A1/SERCA1 ATPase in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+), thereby acting as a key regulator of skeletal muscle activity.

This gene encodes a small peptide that shares structural similarity to the small peptides sarcolipin and phospholamban, which are key regulators of sarcoplasmic reticulum Ca(2+)-ATPases (SERCAs). This protein is thought to have a similar function to these peptides, regulating Ca(2+) reuptake in the sarcoplasmic reticulum by inhibiting the Ca(2+) pump activity of SERCAs. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 100507027 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_001304731

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:48649
Approved symbol	MRLN
Name	myoregulin
Location	10q21.2
Locus type	gene with protein product
Status	Approved
Aliases	M1, MUSER1, MLN, Linc-RAM
Ensembl gene	ENSG00000227877
Ensembl biotype	protein_coding
OMIM	616246
Entrez	100507027

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000414264, ENST00000430431, ENST00000594536, ENST00000598384, ENST00000599605, ENST00000600486, ENST00000602051, ENST00000612853, ENST00000621566, ENST00000628562, ENST00000629130

RefSeq mRNA: 2 — MANE Select: NM_001304731 NM_001304731, NM_001304732

CCDS: CCDS81467

Canonical transcript exons

ENST00000414264 — 3 exons

Exon	Start	End
ENSE00001603592	59738459	59738562
ENSE00003764407	59736692	59737220
ENSE00003893748	59753354	59753455

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 98.50.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0878 / max 351.5308, expressed in 87 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109473	0.6384	72
109472	0.1373	37
109470	0.1334	41
109471	0.0859	23
109469	0.0805	29
109474	0.0123	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	98.50	gold quality
tibialis anterior	UBERON:0001385	98.45	gold quality
quadriceps femoris	UBERON:0001377	97.88	gold quality
vastus lateralis	UBERON:0001379	97.75	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.75	gold quality
skeletal muscle tissue	UBERON:0001134	97.27	gold quality
deltoid	UBERON:0001476	97.19	gold quality
gastrocnemius	UBERON:0001388	97.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.35	gold quality
body of tongue	UBERON:0011876	96.34	gold quality
muscle of leg	UBERON:0001383	95.95	gold quality
cerebellar hemisphere	UBERON:0002245	90.26	gold quality
cerebellar cortex	UBERON:0002129	90.25	gold quality
cerebellum	UBERON:0002037	89.84	gold quality
muscle tissue	UBERON:0002385	88.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.13	gold quality
tongue	UBERON:0001723	86.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.66	silver quality
bronchial epithelial cell	CL:0002328	84.35	silver quality
right uterine tube	UBERON:0001302	83.90	gold quality
kidney epithelium	UBERON:0004819	82.60	gold quality
bronchus	UBERON:0002185	82.58	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.60	gold quality
islet of Langerhans	UBERON:0000006	81.60	gold quality
cerebellar vermis	UBERON:0004720	80.73	gold quality
pituitary gland	UBERON:0000007	75.73	gold quality
oviduct epithelium	UBERON:0004804	74.21	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.95	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.41
E-GEOD-81547	yes	5.74

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• The human and mouse MLN genes consist of three exons that span 16.5 and 15.0 kb, respectively, with the ORF located in exon 3; findings identify MLN as an important regulator of skeletal muscle physiology. (PMID:25640239)
• downregulation of Linc-RAM lncRNA may participate in FGF-2 mediated- proliferation of human PDLSCs (PMID:31378921)
• Functional Role of an Unusual Transmembrane Acidic Residue in the Calcium Pump Regulator Myoregulin. (PMID:37014032)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mrln	ENSMUSG00000019933
rattus_norvegicus	Mrln	ENSRNOG00000069916

Protein

Protein identifiers

Myoregulin — P0DMT0 (reviewed: P0DMT0)

All UniProt accessions (1): P0DMT0

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits the activity of ATP2A1/SERCA1 ATPase in sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+), thereby acting as a key regulator of skeletal muscle activity. Its high expression in adult skeletal muscle, suggests that it constitutes the predominant regulator of ATP2A1/SERCA1 in adult skeletal muscle. Also inhibits the activity of ATP2A2/SERCA2 and ATP2A3/SERCA3.

Subunit / interactions. Homooligomer. Monomer. Interacts with ATP2A1/SERCA1. Interacts as a monomer with ATP2A2/SERCA2; the interaction inhibits ATP2A2 activity.

Subcellular location. Sarcoplasmic reticulum membrane.

RefSeq proteins (2): NP_001291660, NP_001291661 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR049526	Myoregulin	Family

UniProt features (4 total): topological domain 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DMT0-F1	81.26	0.55

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MORF_ATRX, chr10q21, MORF_ESR1, GOBP_MONOATOMIC_CATION_TRANSPORT, BROWNE_HCMV_INFECTION_48HR_DN, REACTOME_PEPTIDE_LIGAND_BINDING_RECEPTORS, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_SARCOPLASMIC_RETICULUM_CALCIUM_ION_TRANSPORT, MORF_ETV3, AACTTT_UNKNOWN, MYB_Q3, GOBP_NEGATIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING

GO Biological Process (1): negative regulation of calcium ion import into sarcoplasmic reticulum (GO:1902081)

GO Molecular Function (1): enzyme inhibitor activity (GO:0004857)

GO Cellular Component (3): sarcoplasmic reticulum membrane (GO:0033017), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of intracellular transport	1
negative regulation of calcium ion transport	1
regulation of calcium ion import into sarcoplasmic reticulum	1
calcium ion import into sarcoplasmic reticulum	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
bounding membrane of organelle	1
cellular anatomical structure	1
endoplasmic reticulum	1
sarcoplasm	1

Protein interactions and networks

STRING

212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRLN	MYOD1	P15172	958
MRLN	STRIT1	P0DN84	871
MRLN	SLN	O00631	756
MRLN	ERLN	P0DI80	714
MRLN	SPAAR	A0A1B0GVQ0	691
MRLN	ARLN	Q8WVX3	677
MRLN	SMARCD3	Q6STE5	660
MRLN	NBDY	A0A0U1RRE5	583
MRLN	ATP2A1	O14983	582
MRLN	SMARCA4	P51532	537
MRLN	MTLN	Q8NCU8	507
MRLN	SMIM22	K7EJ46	476
MRLN	KDM1A	O60341	465
MRLN	MYOG	P15173	418
MRLN	MIEF1	L0R8F8	397

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0ZZ51, A1JU92, O68693, P0C2M7, P0CK19, P0CK23, P0DMT0, P0DPN1, P0DTM7, P20557, P41616, P46613, P51072, P62097, P62099, Q03783, Q06GY1, Q09MG2, Q09X01, Q0G9U6, Q14FE1, Q2L918, Q2PMR8, Q3BAM4, Q49KY3, Q5SD42, Q67H89, Q67H93, Q67H97, Q67HC1, Q67HH3, Q68RZ0, Q6EYP2, Q6EYR0, Q6EYS6, Q6EYU4, Q6EYV1, Q6EYV9, Q6Q1S0, Q6YLT4

Diamond homologs: P0DMT0, Q9CV60

SIGNOR signaling

0 interactions.

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

1058 predictions. Top by Δscore:

Variant	Effect	Δscore
10:59738290:T:A	donor_gain	1.0000
6:33801041:TCTTA:T	donor_loss	1.0000
6:33801042:CTTA:C	donor_loss	1.0000
6:33801043:TTAC:T	donor_loss	1.0000
6:33801044:TACC:T	donor_loss	1.0000
6:33801045:ACC:A	donor_loss	1.0000
6:33801168:GAGC:G	acceptor_loss	1.0000
6:33801171:C:CA	acceptor_loss	1.0000
6:33801171:C:CC	acceptor_gain	1.0000
6:33801172:T:A	acceptor_loss	1.0000
6:33803945:CTACT:C	donor_loss	1.0000
6:33803946:TACTT:T	donor_loss	1.0000
6:33803947:ACTTA:A	donor_loss	1.0000
6:33803948:CTTAC:C	donor_loss	1.0000
6:33803949:TTACG:T	donor_loss	1.0000
6:33803950:TAC:T	donor_loss	1.0000
6:33803951:A:AC	donor_gain	1.0000
6:33803951:A:C	donor_loss	1.0000
6:33803951:ACGG:A	donor_gain	1.0000
6:33803952:C:CA	donor_gain	1.0000
6:33803952:CG:C	donor_gain	1.0000
6:33803952:CGG:C	donor_gain	1.0000
6:33803952:CGGC:C	donor_gain	1.0000
10:59738453:TCTCA:T	donor_loss	0.9900
10:59738454:CTCAC:C	donor_loss	0.9900
10:59738455:TCACC:T	donor_loss	0.9900
10:59738456:CACC:C	donor_loss	0.9900
10:59738457:A:C	donor_loss	0.9900
10:59738562:CCTG:C	acceptor_gain	0.9900
10:59738563:C:CC	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000340176 (10:59737275 T>G), RS1000406158 (10:59737539 A>G), RS1000627155 (10:59736208 C>T), RS1000776962 (10:59743270 C>G,T), RS1000839565 (10:59744044 C>T), RS1000902463 (10:59748221 C>G), RS1000947975 (10:59744320 G>A,C), RS1001062470 (10:59744196 G>A), RS1001149564 (10:59753670 A>C,T), RS1001210676 (10:59742941 G>A), RS1001416736 (10:59737351 T>C), RS1001518765 (10:59753916 T>G), RS1001531494 (10:59736989 A>G), RS1001629163 (10:59743811 C>T), RS1001700532 (10:59749435 C>G,T)

Disease associations

OMIM: gene MIM:616246 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000426_4	Obesity (extreme)	6.000000e-06
GCST000703_3	Phosphorus levels	1.000000e-11
GCST001280_9	Alzheimer’s disease (age of onset)	7.000000e-06
GCST001762_714	Obesity-related traits	8.000000e-06
GCST002094_5	Crohn’s disease	1.000000e-08
GCST005830_42	Hand grip strength	4.000000e-08
GCST005951_153	Body mass index	5.000000e-09
GCST006585_1802	Blood protein levels	4.000000e-79
GCST006920_1	Regular attendance at a gym or sports club	4.000000e-08
GCST007656_5	Chronic obstructive pulmonary disease or resting heart rate (pleiotropy)	3.000000e-15
GCST008362_154	Birth weight	6.000000e-12
GCST008512_16	Multisite chronic pain	3.000000e-10
GCST008919_7	Asthma and attention deficit hyperactivity disorder	4.000000e-08
GCST012332_75	Multisite chronic pain	1.000000e-09
GCST012332_76	Multisite chronic pain	1.000000e-09
GCST90000514_5	Gastroesophageal reflux disease	3.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004861	phosphorus measurement
EFO:0004847	age at onset
EFO:0003939	energy intake
EFO:0006941	grip strength measurement
EFO:0004340	body mass index
EFO:0009592	social interaction measurement
EFO:0004344	birth weight
EFO:0010100	multisite chronic pain

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2894342	MLN		0.00	0

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
incobotulinumtoxinA	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Methapyrilene	decreases methylation	1
Smoke	increases abundance, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cadmium Chloride	increases abundance, increases expression	1

Clinical trials (associated diseases)

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