CSH1

Summary

CSH1 (chorionic somatomammotropin hormone 1, HGNC:2440) is a protein-coding gene on chromosome 17q23.3, encoding Chorionic somatomammotropin hormone 1 (P0DML2). Produced only during pregnancy and is involved in stimulating lactation, fetal growth and metabolism.

The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones and plays an important role in growth control. The gene is located at the growth hormone locus on chromosome 17 along with four other related genes in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. Although the five genes share a remarkably high degree of sequence identity, they are expressed selectively in different tissues. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed mainly in the placenta and utilizes multiple transcription initiation sites. Expression of the identical mature proteins for chorionic somatomammotropin hormones 1 and 2 is upregulated during development, although the ratio of 1 to 2 increases by term. Mutations in this gene result in placental lactogen deficiency and Silver-Russell syndrome.

Source: NCBI Gene 1442 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 38 total
• MANE Select transcript: NM_001317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2440
Approved symbol	CSH1
Name	chorionic somatomammotropin hormone 1
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	hCS-A, CSA, PL, CSMT, FLJ75407
Ensembl gene	ENSG00000136488
Ensembl biotype	protein_coding
OMIM	150200
Entrez	1442

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 retained_intron

ENST00000316193, ENST00000329882, ENST00000453363, ENST00000558284, ENST00000558661, ENST00000610991

RefSeq mRNA: 1 — MANE Select: NM_001317 NM_001317

CCDS: CCDS11649

Canonical transcript exons

ENST00000316193 — 5 exons

Exon	Start	End
ENSE00002449213	63895731	63895850
ENSE00002468625	63895473	63895637
ENSE00002504378	63896502	63896574
ENSE00002522073	63896075	63896235
ENSE00002559899	63894918	63895219

Expression profiles

Bgee: expression breadth broad, 44 present calls, max score 99.88.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3750 / max 284.7748, expressed in 6 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167508	0.1795	6
167507	0.1081	4
208315	0.0485	3
167506	0.0362	3
208314	0.0027	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	99.88	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.50	gold quality
adenohypophysis	UBERON:0002196	83.77	gold quality
pituitary gland	UBERON:0000007	83.68	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.60	gold quality
smooth muscle tissue	UBERON:0001135	67.29	gold quality
monocyte	CL:0000576	53.39	gold quality
leukocyte	CL:0000738	51.58	gold quality
duodenum	UBERON:0002114	49.62	gold quality
muscle tissue	UBERON:0002385	43.94	gold quality
colonic epithelium	UBERON:0000397	41.35	gold quality
cortical plate	UBERON:0005343	40.26	gold quality
sural nerve	UBERON:0015488	38.97	gold quality
adrenal tissue	UBERON:0018303	38.81	gold quality
tonsil	UBERON:0002372	38.63	gold quality
bone marrow cell	CL:0002092	38.27	gold quality
lower esophagus mucosa	UBERON:0035834	37.87	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
granulocyte	CL:0000094	35.53	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
bone marrow	UBERON:0002371	32.82	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
vermiform appendix	UBERON:0001154	30.93	gold quality
urinary bladder	UBERON:0001255	30.77	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
blood	UBERON:0000178	29.44	silver quality
brain	UBERON:0000955	28.51	gold quality
myometrium	UBERON:0001296	28.44	gold quality
cerebellum	UBERON:0002037	28.40	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-23	yes	21675.28
E-MTAB-6678	yes	15358.56
E-MTAB-6701	yes	11059.05
E-ANND-3	no	0.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPB, FOXM1, HAND1, ID2, NFIC, NR3C1, PITX2, POU1F1, RFX1, SP1, TFAP2A

miRNA regulators (miRDB)

6 targeting CSH1, 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-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280

Literature-anchored findings (GeneRIF, showing 22)

• Investigation of the GRB2, GRB7, and CSH1 genes as candidates for the Silver-Russell syndrome (SRS) on chromosome 17q. (PMID:11897833)
• a role for CSH1 haploinsufficiency in the etiology of growth retardation (PMID:14642004)
• These data implicate ETS-domain family members in the regulation of the CS locus in placenta and pituitary cells. (PMID:14673137)
• We showed that intra-arterial infusion of human placental lactogen primarily decreased coronary, renal & iliac blood flow. Mechanism of this response was shown to be due to inhibition of vasodilatory beta2-adrenergic receptor-mediated effect. (PMID:16410683)
• crystal structure of the free state of human PL has been determined to 2.0 A resolution showing the molecule possesses an overall structure similar to other long chain four-helix bundle cytokines (PMID:16546209)
• The present findings indicate that the concentration of human placental lactogen (hPL) and human chorionic gonadotropin (beta hCG) mRNA is significantly higher in the cellular component of maternal blood samples than in the plasma component. (PMID:16950818)
• A CSH1 deletion carrier with nearly complete hypomethylation at the ICR1 locus had the characteristic clinical signs of Silver Russel syndrome, ruling out a causal relationship. (PMID:17400796)
• Placental lactogen is a novel ligand of stabilin-1. (PMID:18292525)
• Three single nucleotide polymorphisms in CGB5 and CSH1 genes were genotyped for 844 offspring of the cases and controls. Maternal breast cancer risk did not significantly differ by the offspring’s carrier status of the three SNPs. (PMID:19047151)
• maternal smoking associated with a reduction in cord blood hPL (PMID:19290844)
• The human growth hormone/chorionic somatomammotropin at chromosome 17 is implicated in regulation of postnatal and intrauterine growth. (PMID:20233782)
• Results strongly support a conformationally mediated obligate-ordered prolactin receptor binding for each of the three lactogenic hormones: prolactin, growth hormone, and placental lactogen. (PMID:20427283)
• Data conclude that members of the C/EBP and Ets families can differentially modulate CS-Benh and CS-Aenh activity. (PMID:21737519)
• hPL-A is involved in the regulation of pancreatic beta cells activity. (PMID:21765243)
• results are consistent with a pleiotropic effect of placental hGH/CSH genes at the maternal-fetal interface relating to the regulation of fetal growth and the risk of affected maternal metabolism. (PMID:22387044)
• altered expression of placenta lactogen appears not to be causal for betamethasone-induced fetal growth restriction in the human (PMID:23465880)
• Expression of placental lactogen mRNA is increased in plasma of women with placenta previa and invasive placenta. (PMID:23744883)
• These results indicate that placental lactogen induces CYP2E1 expression via PI3-kinase pathway in human hepatocytes. (PMID:24408518)
• Placental lactogen is expressed but is not translated into protein in breast cancer. (PMID:24475273)
• FGF-2b and hPL-A are promising candidates for regenerative therapy in Diabetes Mellitus by inducing de-differentiation of stem cells modulating pivotal endocrine genes. (PMID:29068419)
• Obesity and regulation of human placental lactogen production in pregnancy. (PMID:32500948)
• Plasmin generates vasoinhibin-like peptides by cleaving prolactin and placental lactogen. (PMID:34601001)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gh1	ENSDARG00000038185
mus_musculus	Gh	ENSMUSG00000020713
rattus_norvegicus	Gh1	ENSRNOG00000011207

Paralogs (5): GH2 (ENSG00000136487), PRL (ENSG00000172179), CSHL1 (ENSG00000204414), CSH2 (ENSG00000213218), GH1 (ENSG00000259384)

Protein

Protein identifiers

Chorionic somatomammotropin hormone 1 — P0DML2 (reviewed: P0DML2)

Alternative names: Lactogen, Placental lactogen

All UniProt accessions (5): A0A087WUG6, A6NFB4, A8K6C2, B1A4H2, P0DML2

UniProt curated annotations — full annotation on UniProt →

Function. Produced only during pregnancy and is involved in stimulating lactation, fetal growth and metabolism. Does not interact with GHR but only activates PRLR through zinc-induced dimerization.

Subunit / interactions. Can be found in a monomeric as well as dimeric form.

Subcellular location. Secreted.

Miscellaneous. CSH1 sequence only differs from CSH2 sequence in 1 aa.

Similarity. Belongs to the somatotropin/prolactin family.

RefSeq proteins (1): NP_001308* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001400	Somatotropin/Prolactin	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR018116	Somatotropin_CS	Conserved_site
IPR034975	Somatotropin	Family

Pfam: PF00103

UniProt features (24 total): helix 8, sequence conflict 4, disulfide bond 4, turn 3, binding site 2, signal peptide 1, chain 1, strand 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1Z7C	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DML2-F1	82.67	0.49

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 44; 200

Disulfide bonds (4): 79–191, 208–215, 208, 215

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1170546	Prolactin receptor signaling
R-HSA-982772	Growth hormone receptor signaling

MSigDB gene sets: 75 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_GROWTH_HORMONE, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_HORMONE, GNF2_KISS1

GO Biological Process (5): response to nutrient levels (GO:0031667), positive regulation of receptor signaling pathway via JAK-STAT (GO:0046427), animal organ development (GO:0048513), growth hormone receptor signaling pathway (GO:0060396), signal transduction (GO:0007165)

GO Molecular Function (5): growth hormone receptor binding (GO:0005131), hormone activity (GO:0005179), growth factor activity (GO:0008083), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endosome lumen (GO:0031904), vesicle (GO:0031982), cytoplasm (GO:0005737), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cytokine Signaling in Immune system	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
receptor ligand activity	2
response to stimulus	1
cell surface receptor signaling pathway via JAK-STAT	1
regulation of receptor signaling pathway via JAK-STAT	1
positive regulation of receptor signaling pathway via STAT	1
anatomical structure development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to growth hormone stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cytokine receptor binding	1
hormone receptor binding	1
cation binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
endosome	1
intracellular organelle lumen	1
membrane-bounded organelle	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

12 interactions, top by confidence:

A	B	Type	Score
PSMD9	CSH1	psi-mi:“MI:0407”(direct interaction)	0.610
CSH1	PSMD9	psi-mi:“MI:0407”(direct interaction)	0.610
PSMD9	CSH1	psi-mi:“MI:0915”(physical association)	0.610
CSH1	SGTB	psi-mi:“MI:0915”(physical association)	0.560
CSH1	GH1	psi-mi:“MI:0914”(association)	0.350
CSH1	H6PD	psi-mi:“MI:0914”(association)	0.350
CSH1	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): CSH1 (Reconstituted Complex), CSH1 (Protein-peptide), CSH2 (Affinity Capture-MS), GH1 (Affinity Capture-MS), CSH2 (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), SGTB (Two-hybrid), CINP (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), GH1 (Affinity Capture-MS), CSHL1 (Affinity Capture-MS), PADI2 (Affinity Capture-MS), H6PD (Affinity Capture-MS), KLHL8 (Affinity Capture-MS), CSH1 (Two-hybrid)

ESM2 similar proteins: A0S0B0, A3FBE9, B6CKP4, O73848, P01241, P01244, P05231, P06880, P08505, P08998, P09321, P09586, P09611, P0DML2, P0DML3, P11228, P14188, P16038, P19795, P20294, P20607, P22077, P26441, P37886, P41683, P43431, P46650, P51494, P51642, P58343, P58756, P58757, P79341, Q07370, Q0GGL7, Q14406, Q25BC2, Q28819, Q2XNF5, Q5I6E3

Diamond homologs: O12980, O13188, O18938, O62754, O70615, O73848, O73849, O93359, O93360, P01241, P01242, P01244, P01245, P01246, P01248, P06880, P07064, P08591, P08899, P08998, P09113, P09538, P0DML2, P0DML3, P10298, P10607, P10766, P10813, P10814, P11228, P12855, P12856, P19795, P20332, P20391, P20392, P22077, P26773, P26774, P29971

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

617 predictions. Top by Δscore:

Variant	Effect	Δscore
17:63895215:AGCCT:A	acceptor_gain	1.0000
17:63895216:GCCT:G	acceptor_gain	1.0000
17:63895217:CCTC:C	acceptor_gain	1.0000
17:63895218:CT:C	acceptor_gain	1.0000
17:63895220:C:CC	acceptor_gain	1.0000
17:63895220:CT:C	acceptor_loss	1.0000
17:63895221:T:A	acceptor_loss	1.0000
17:63895227:G:C	acceptor_gain	1.0000
17:63895227:G:GC	acceptor_gain	1.0000
17:63895471:ACCC:A	donor_gain	1.0000
17:63895472:CCCC:C	donor_gain	1.0000
17:63895474:C:CA	donor_gain	1.0000
17:63895496:C:A	donor_gain	1.0000
17:63895501:AGGT:A	donor_gain	1.0000
17:63895504:T:TA	donor_gain	1.0000
17:63895566:ACT:A	donor_gain	1.0000
17:63895567:CTC:C	donor_gain	1.0000
17:63895636:TT:T	acceptor_gain	1.0000
17:63895727:TCAC:T	donor_loss	1.0000
17:63895728:CAC:C	donor_loss	1.0000
17:63895729:A:AC	donor_gain	1.0000
17:63895729:AC:A	donor_loss	1.0000
17:63895730:C:CC	donor_gain	1.0000
17:63895730:CGG:C	donor_gain	1.0000
17:63896073:A:AC	donor_gain	1.0000
17:63896074:C:CC	donor_gain	1.0000
17:63896074:CAAA:C	donor_gain	1.0000
17:63895219:TCTGC:T	acceptor_gain	0.9900
17:63895223:C:CT	acceptor_gain	0.9900
17:63895224:A:T	acceptor_gain	0.9900

AlphaMissense

1430 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:63895070:G:C	F202L	0.959
17:63895070:G:T	F202L	0.959
17:63895072:A:G	F202L	0.959
17:63896075:A:C	F57L	0.941
17:63896075:A:T	F57L	0.941
17:63896077:A:G	F57L	0.941
17:63895101:A:G	F192S	0.937
17:63895593:C:A	W112C	0.933
17:63895593:C:G	W112C	0.933
17:63895100:G:C	F192L	0.927
17:63895100:G:T	F192L	0.927
17:63895102:A:G	F192L	0.927
17:63895092:T:G	D195A	0.921
17:63895627:A:G	L101P	0.919
17:63895093:C:G	D195H	0.916
17:63895595:A:G	W112R	0.916
17:63895595:A:T	W112R	0.916
17:63896097:G:T	A50D	0.914
17:63895160:A:C	F172L	0.910
17:63895160:A:T	F172L	0.910
17:63895162:A:G	F172L	0.910
17:63895091:G:C	D195E	0.904
17:63895091:G:T	D195E	0.904
17:63895053:C:G	C208S	0.903
17:63895054:A:T	C208S	0.903
17:63895615:G:A	S105F	0.903
17:63896076:A:C	F57C	0.898
17:63895624:A:T	L102H	0.894
17:63895068:A:G	L203P	0.893
17:63895025:G:C	F217L	0.885

dbSNP variants (sampled 300 via entrez): RS1000733524 (17:63894773 A>G), RS1000766451 (17:63894958 T>A,C), RS1002643687 (17:63897979 C>T), RS1003085858 (17:63898287 C>A), RS1003686574 (17:63897329 T>C), RS1006529038 (17:63898412 T>C), RS1007524120 (17:63897482 G>C,T), RS1011333397 (17:63897752 G>C,T), RS1012334183 (17:63896571 C>A,G,T), RS1012448356 (17:63897105 T>C,G), RS1015370036 (17:63896822 T>C), RS1017861134 (17:63898413 G>T), RS1018246896 (17:63898327 G>C,T), RS1018832255 (17:63897397 A>C,G), RS1019280006 (17:63897487 G>T)

Disease associations

OMIM: gene MIM:150200 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001956_56	Height	3.000000e-14
GCST002702_79	Height	2.000000e-12
GCST008839_225	Height	5.000000e-22

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Colforsin	decreases expression, increases reaction, affects cotreatment	2
Valproic Acid	decreases expression, increases reaction, affects cotreatment, increases methylation	2
propionaldehyde	decreases expression	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
afimoxifene	decreases reaction, decreases expression	1
cobaltous chloride	decreases expression, increases reaction	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression	1
Arsenic Trioxide	decreases expression	1
Ethanol	decreases expression	1
Fonofos	increases methylation	1
Estrogens	decreases expression, decreases reaction	1
Hydrogen Peroxide	affects expression	1
Parathion	increases methylation	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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