PTHLH

Summary

PTHLH (parathyroid hormone like hormone, HGNC:9607) is a protein-coding gene on chromosome 12p11.22, encoding Parathyroid hormone-related protein (P12272). Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the parathyroid hormone family. This hormone, via its receptor, PTHR1, regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. It is responsible for most cases of humoral hypercalcemia of malignancy, and mutations in this gene are associated with brachydactyly type E2 (BDE2). Alternatively spliced transcript variants have been found for this gene. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, downstream of the initiator AUG codon, resulting in nuclear forms of this hormone.

Source: NCBI Gene 5744 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brachydactyly type E2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 25
• Clinical variants (ClinVar): 130 total — 15 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity little evidence
• MANE Select transcript: NM_198965

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9607
Approved symbol	PTHLH
Name	parathyroid hormone like hormone
Location	12p11.22
Locus type	gene with protein product
Status	Approved
Aliases	PTHRP, HHM, PLP, PTHR
Ensembl gene	ENSG00000087494
Ensembl biotype	protein_coding
OMIM	168470
Entrez	5744

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000201015, ENST00000395868, ENST00000395872, ENST00000534890, ENST00000535992, ENST00000538310, ENST00000539239, ENST00000542963, ENST00000545234, ENST00000851935, ENST00000963668, ENST00000963669, ENST00000963670

RefSeq mRNA: 4 — MANE Select: NM_198965 NM_002820, NM_198964, NM_198965, NM_198966

CCDS: CCDS44853, CCDS8715

Canonical transcript exons

ENST00000545234 — 6 exons

Exon	Start	End
ENSE00001188730	27963348	27963770
ENSE00001523130	27958084	27958568
ENSE00001647300	27970025	27970267
ENSE00002229585	27971927	27972019
ENSE00002305048	27972523	27972733
ENSE00003550796	27969394	27969516

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 92.23.

FANTOM5 (CAGE): breadth broad, TPM avg 11.7696 / max 1364.9074, expressed in 848 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130272	3.9721	90
130264	3.6768	275
130268	2.6378	687
130265	0.4884	146
130266	0.2732	132
130271	0.2256	41
130267	0.1814	87
130269	0.1029	54
206658	0.0878	44
130270	0.0697	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	92.23	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.79	gold quality
stromal cell of endometrium	CL:0002255	84.98	gold quality
ectocervix	UBERON:0012249	82.61	gold quality
endocervix	UBERON:0000458	80.31	gold quality
endothelial cell	CL:0000115	79.43	gold quality
vagina	UBERON:0000996	79.09	gold quality
descending thoracic aorta	UBERON:0002345	78.02	gold quality
ascending aorta	UBERON:0001496	77.79	gold quality
gall bladder	UBERON:0002110	77.74	gold quality
thoracic aorta	UBERON:0001515	77.73	gold quality
prefrontal cortex	UBERON:0000451	77.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.56	gold quality
cingulate cortex	UBERON:0003027	75.77	gold quality
anterior cingulate cortex	UBERON:0009835	75.52	gold quality
esophagus mucosa	UBERON:0002469	75.40	gold quality
choroid plexus epithelium	UBERON:0003911	75.25	gold quality
minor salivary gland	UBERON:0001830	75.23	gold quality
aorta	UBERON:0000947	74.43	gold quality
uterine cervix	UBERON:0000002	73.69	gold quality
epithelium of mammary gland	UBERON:0003244	73.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	72.41	gold quality
popliteal artery	UBERON:0002250	72.27	gold quality
tibial artery	UBERON:0007610	72.26	gold quality
mammary duct	UBERON:0001765	71.82	gold quality
mouth mucosa	UBERON:0003729	71.66	gold quality
esophagus	UBERON:0001043	71.28	gold quality
saliva-secreting gland	UBERON:0001044	70.63	gold quality
amygdala	UBERON:0001876	70.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	70.11	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.00
E-CURD-10	no	122.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, BCL3, CEBPB, CREB1, EGR4, EPAS1, ETS1, ETS2, FOXN1, GLI1, GLI2, GLI3, JUN, NFIL3, NFKB1, NFKB, NR3C1, REL, RELA, RUNX2, SMAD3, SMAD4, SOX5, SOX6, SOX9, SP1, SP7, SPOP, TCF3, TFAP2A, TP53, VDR, ZEB1

miRNA regulators (miRDB)

60 targeting PTHLH, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4524A-3P	99.72	66.85	2406

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Translation initiation from non-AUG (CUG) start sites in the signal sequence, downstream of the initiator AUG codon, target PTHrP molecules exclusively to the nucleoli. (PMID:10873655)
• Alternative, in-frame translation initiation from non-AUG (CUG and GUG) start sites, downstream of the initiator AUG, give rise to nuclear forms of parathyroid hormone-related protein. (PMID:11159841)
• Data show that parathyroid hormone-related protein (PTHrP) mRNA and secreted protein levels are downregulated by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) via a transcriptional mechanism. (PMID:11997185)
• Autocrine/paracrine involvement of parathyroid hormone-related peptide in vascular leiomyoma. (PMID:12201218)
• Results indicate the presence of a PTH/PTHrP responsive element in the human COL10A1 enhancer. (PMID:12210735)
• findings suggest that beta-arrestin 1 acts as an effector for a novel function of PTHrP in cytoplasm (PMID:12220636)
• vascular sites of expression of PTHrP and its cognate receptor in the rheumatoid synovium and/or in cultured rheumatoid synovial endothelial cells (PMID:12359237)
• first report demonstrating that PTHrP is produced in the myocardium and is increased in congestive heart failure (PMID:12364464)
• PTHRP and its receptor are co-expressed more frequently in bone metastases of breast cancer (PMID:12374685)
• Cytotoxic T-lymphocyte lines generated using PTH-rP peptide-pulsed dendritic cells have epitope peptide specificity, HLA-A(*)02.01 restriction, and the ability to kill HLA-A(*)02.01/PTH-rP-producing cancer cells. (PMID:12391194)
• In conclusion, breast fibroblasts are constitutive PTHrP-producing cells with the potential for autocrine signaling through the PTH/PTHrP receptor (PMID:12549623)
• PTH-rP may play a significant role in severe hypercalcemia in patients with metastatic melanoma (PMID:12576923)
• results suggest that PTHrP may play a role in prostate tumor invasion and metastasis by influencing cell adhesion to the ECM via upregulation of specific integrin subunits (PMID:12581888)
• androgens can regulate PTHrP production, and the androgen effect on PTHrP is mediated at least in part by transcriptional regulation via the androgen receptor (PMID:12586762)
• results demonstrated a relationship between intensity of parathyroid hormone-related peptide expression and the survival time and development of distant metastases in patients with ductal mammary carcinoma (PMID:12647214)
• Data show that 1,25 vitamin D3 recruited DNA-dependent protein kinase (DNA-PKcs) to the chromatinized negative DNA element of the parathyroid hormone-related polypeptide (PTHrP) gene. (PMID:12727200)
• 1,25-dihydroxyvitamin D3 and non-calcemic analogue EB1089 suppress PTHrP mRNA and protein levels in two prostate cancer cell lines; a PTHrP gene sequence element homologous to the negative vitamin D response element bound the vitamin D receptor (PMID:12850281)
• findings suggest a potential mechanism by which PTHrP transcription may be regulated by Ets-1 as a consequence of events that promote tumorigenic behavior in breast epithelial cells (PMID:12850290)
• replacement of PTHrP prevented the apoptotic changes and reduction of Bcl-2 expression in ATDC5 cells expressing the ACH mutant (PMID:12929929)
• collagenases can be a downstream effector of PTH/PTHrP receptor action in trabecular bone, but not in periosteum. (PMID:12933685)
• PTHRP binds to the extracellular face of the type 1 PTH receptor. (PMID:12947048)
• High plasma levels of PTHrP in cancer-bearing patients contribute to the development of hypercalcemia and syndrome caused by an excess of pro-inflammatory cytokines (PMID:14503917)
• role in programing skeletal development in utero (PMID:14969386)
• Wild-type PTHrP-overexpressing breast cancer cells showed significantly higher laminin adhesion and migration, and Matrigel invasion than empty vector-transfectants or cells overexpressing NLS-mutated PTHrP. (PMID:15023531)
• Data suggest that mitogen-activated protein kinase pathway inactivation regulates parathyroid hormone-related protein (PTHrP)-stimulated AP-1 members, blocks PTHrP-stimulated IL-6, and down-regulates osteoblastic markers associated with differentiation. (PMID:15128746)
• PTHrP increases the percentage of VSM cells in the S & in G2/M phases.These effects require critical serine & threonine residues at positions Ser119, Ser130, Thr132, & Ser138 in the carboxy-terminus of PTHrP & are associated with the PrB phosphorylation. (PMID:15210588)
• PKA appears to have a role in the regulatory effects of PTHrP on lung cancer cell survival. (PMID:15282196)
• Parathyroid hormone-related protein is involved not only in the maternal and fetal failures but also in the etiological aspects of the disease. We hypothesize that reduced local production of the peptide is a major causative event. Review. (PMID:15286039)
• demonstrates cell-type specific expression of PTHrP mRNA isoforms, and disruption of the normal regulation during cancer progression may in part be associated with TGF-beta1-induced changes in PTHrP mRNA isoform expression and stability (PMID:15291755)
• may play a role in colon cancer invasion and metastasis by increasing cell proliferation and adhesion to the ECM via upregulation of proinvasive integrin expression (PMID:15582709)
• that PTHrP expression results in the skeletal progression of prostate cancer cells (PMID:15629138)
• identification of proteins that might bind PTHrP at the cell surface of tumor cells, such as HSPprotein. (PMID:15878959)
• The Parathyroid hormone-related protein (PTHrP) plays a primary role in the development of humoral hypercalcemia of malignancy seen in the majority of adult T-cell leukemia/lymphoma (ATLL) patients with human T-cell lymphotropic virus type-1 infection. (PMID:15889157)
• Production of PTHrP by blast cells was favorably controlled by imatinib therapy alone in chrnoic myelogenous leukemia (PMID:16298826)
• In cancer invasiveness in a breast cancer cell line, a novel humoral fibroblast-breast cancer cell interaction, mediated by PTHrp, can be recognised. (PMID:16455237)
• PTHrP levels decrease in proportion to the severity of heart failure (PMID:16500729)
• PTHrP has a profound effect on gene expression in breast cancer cells and, as a consequence, contributes to the regulation of important cellular activities, such as migration and proliferation (PMID:16551631)
• The role of PTHrP in breast cancer growth and metastasis may be mediated via upregulation of integrin alpha6beta4 expression and Akt activation, with consequent inactivation of GSK-3. (PMID:16965770)
• May be a prognostic marker for bone metastasis in breast cancer. (PMID:17213971)
• identification of PTHrP and ezrin as important regulators of lung cancer bone metastasis offers new mechanistic insights into the metastasis of lung cancer and provides potential targets for the prevention and treatment of lung cancer metastasis (PMID:17370040)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pthlha	ENSDARG00000031737
danio_rerio	pthlhb	ENSDARG00000071070
mus_musculus	Pthlh	ENSMUSG00000048776
rattus_norvegicus	Pthlh	ENSRNOG00000069267

Protein

Protein identifiers

Parathyroid hormone-related protein — P12272 (reviewed: P12272)

Alternative names: Parathyroid hormone-like protein

All UniProt accessions (4): P12272, F5GZD9, F5H485, Q53XY9

UniProt curated annotations — full annotation on UniProt →

Function. Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Acts by binding to its receptor, PTH1R, activating G protein-coupled receptor signaling. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Up-regulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath. Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1-dependent manner through activation of Rac1. Potent inhibitor of osteoclastic bone resorption.

Subunit / interactions. Interacts with PTH1R (via N-terminal extracellular domain).

Subcellular location. Secreted. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Also expressed in the mammary gland.

Post-translational modifications. There are 3 principal secretory forms, called PTHrP[1-36], PTHrP[38-94], and osteostatin (PTHrP[107-139]) arising from endoproteolytic cleavage of the initial translation product. Each of these secretory forms is believed to have one or more of its own receptors that mediates the normal paracrine, autocrine and endocrine actions.

Disease relevance. Brachydactyly E2 (BDE2) [MIM:613382] A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the parathyroid hormone family.

Isoforms (3)

UniProt ID	Names	Canonical?
P12272-1	1	yes
P12272-2	2
P12272-3	3

RefSeq proteins (4): NP_002811, NP_945315, NP_945316, NP_945317 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001415	PTH/PTH-rel	Family
IPR003626	PTH-rel	Family

Pfam: PF01279

UniProt features (28 total): mutagenesis site 6, compositionally biased region 3, sequence variant 3, helix 3, peptide 3, splice variant 2, strand 2, region of interest 2, signal peptide 1, propeptide 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7UZO	X-RAY DIFFRACTION	1.3
3H3G	X-RAY DIFFRACTION	1.94
3FFD	X-RAY DIFFRACTION	2
8D51	X-RAY DIFFRACTION	2
8D52	X-RAY DIFFRACTION	2.02
7UZP	X-RAY DIFFRACTION	2.29
1M5N	X-RAY DIFFRACTION	2.9
8FLR	ELECTRON MICROSCOPY	2.94
7VVJ	ELECTRON MICROSCOPY	3.2
8HAF	ELECTRON MICROSCOPY	3.25
1BZG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P12272-F1	63.65	0.17

Antibody-complex structures (SAbDab): 4 — 3FFD, 7VVJ, 8FLR, 8HAF

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
57	strongly reduced affinity for pth1r.
59	reduced affinity for pth1r.
60	strongly reduced affinity for pth1r.
63	reduced affinity for pth1r.
64	reduced affinity for pth1r.
68	reduced affinity for pth1r.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 354 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP

GO Biological Process (16): skeletal system development (GO:0001501), osteoblast development (GO:0002076), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), cell-cell signaling (GO:0007267), female pregnancy (GO:0007565), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), epidermis development (GO:0008544), regulation of gene expression (GO:0010468), bone mineralization (GO:0030282), regulation of chondrocyte differentiation (GO:0032330), negative regulation of chondrocyte differentiation (GO:0032331), cAMP metabolic process (GO:0046058), negative regulation of chondrocyte development (GO:0061182), adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway (GO:0140582), signal transduction (GO:0007165)

GO Molecular Function (3): hormone activity (GO:0005179), peptide hormone receptor binding (GO:0051428), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
GPCR ligand binding	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell communication	2
signaling	2
cell population proliferation	2
regulation of cell population proliferation	2
chondrocyte differentiation	2
cytoplasm	2
intracellular membrane-bounded organelle	2
system development	1
osteoblast differentiation	1
cell development	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
multi-organism reproductive process	1
multi-multicellular organism process	1
positive regulation of cellular process	1
negative regulation of cellular process	1
tissue development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
ossification	1
biomineral tissue development	1
regulation of cell differentiation	1
regulation of cartilage development	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
purine ribonucleotide metabolic process	1
cyclic purine nucleotide metabolic process	1
chondrocyte development	1
negative regulation of cell development	1
negative regulation of chondrocyte differentiation	1
regulation of chondrocyte development	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
hormone receptor binding	1
binding	1

Protein interactions and networks

STRING

1580 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTHLH	PTH1R	Q03431	999
PTHLH	PTH	P01270	999
PTHLH	IHH	Q14623	956
PTHLH	PTH2R	P49190	952
PTHLH	TNFSF11	O14788	783
PTHLH	FGF2	P09038	780
PTHLH	FGF13	Q92913	758
PTHLH	IL11	P20809	745
PTHLH	COL2A1	P02458	745
PTHLH	CASR	P41180	744
PTHLH	KLK3	P07288	733
PTHLH	RUNX2	Q13950	713
PTHLH	BMP2	P12643	695
PTHLH	SHH	Q15465	670
PTHLH	GLI1	P08151	668

IntAct

7 interactions, top by confidence:

A	B	Type	Score
PTH1R	PTHLH	psi-mi:“MI:0407”(direct interaction)	0.610
PTH1R	PTH	psi-mi:“MI:0915”(physical association)	0.610
PTHLH	E7	psi-mi:“MI:0915”(physical association)	0.370
PLK1	ERCC6L	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): PTHLH (Protein-RNA), PTHLH (Reconstituted Complex), KPNB1 (Reconstituted Complex), KPNB1 (Co-crystal Structure), KPNB1 (Reconstituted Complex), ARRB1 (Two-hybrid), ARRB1 (Reconstituted Complex), PTHLH (Reconstituted Complex), PTHLH (Co-crystal Structure), PTHLH (Two-hybrid), PTHLH (Affinity Capture-MS), ELAVL1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1L2F565, B3IWF7, B3IWF9, D3Z752, E2E4E4, F1QQI2, I7C2V3, M0R8L2, O46540, O62647, O73812, O93448, P01146, P01257, P01258, P07501, P0DQY8, P10093, P12272, P12969, P15743, P22858, P27104, P47851, P51918, P52211, P58073, P63152, P63292, P70160, P81564, P81872, Q0VBW8, Q0VC44, Q13519, Q5H8A3, Q60549, Q64387, Q75V94, Q75V95

Diamond homologs: A0A1L2F565, P12272, P13085, P17251, P22858, P52211, P58073, Q9GK30, Q9GLC7, Q9GMB7

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	PTHLH	phosphorylation
CDK2	down-regulates	PTHLH	phosphorylation
KLK3	“down-regulates activity”	PTHLH	cleavage
KLK3	“up-regulates activity”	PTHLH	binding
PTHLH	“up-regulates activity”	PTH1R	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	8
Uncertain significance	69
Likely benign	27
Benign	4

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1192234	NM_198965.2(PTHLH):c.44T>G (p.Leu15Arg)	Pathogenic
13738	NM_198965.2(PTHLH):c.179T>C (p.Leu60Pro)	Pathogenic
13739	NM_198965.2(PTHLH):c.131T>C (p.Leu44Pro)	Pathogenic
13740	NM_198965.2(PTHLH):c.534A>G (p.Ter178Trp)	Pathogenic
13741	NM_198965.2(PTHLH):c.358A>T (p.Lys120Ter)	Pathogenic
1435513	NM_198965.2(PTHLH):c.207del (p.Ala70fs)	Pathogenic
1451145	NM_198965.2(PTHLH):c.309C>G (p.Tyr103Ter)	Pathogenic
1458784	NC_000012.11:g.(?28111492)(28122427_?)del	Pathogenic
1459726	NC_000012.11:g.(?28111492)(28122427_?)dup	Pathogenic
2109885	NM_198965.2(PTHLH):c.54C>A (p.Tyr18Ter)	Pathogenic
2152144	NM_198965.2(PTHLH):c.169C>T (p.Arg57Ter)	Pathogenic
2704575	NM_198965.2(PTHLH):c.178_181del (p.Leu60fs)	Pathogenic
3362250	NM_198965.2(PTHLH):c.166C>T (p.Arg56Ter)	Pathogenic
3638473	NM_198965.2(PTHLH):c.227C>A (p.Ser76Ter)	Pathogenic
3894530	NM_198965.2(PTHLH):c.4C>T (p.Gln2Ter)	Pathogenic
2036140	NM_198965.2(PTHLH):c.1A>T (p.Met1Leu)	Likely pathogenic
2811749	NM_198965.2(PTHLH):c.2T>C (p.Met1Thr)	Likely pathogenic
2832630	NM_198965.2(PTHLH):c.1A>G (p.Met1Val)	Likely pathogenic
3256666	NM_198965.2(PTHLH):c.276dup (p.Val93fs)	Likely pathogenic
3376415	NM_198965.2(PTHLH):c.54C>G (p.Tyr18Ter)	Likely pathogenic
3382184	NM_198965.2(PTHLH):c.463_464del (p.Ser155fs)	Likely pathogenic
3730518	NM_198965.2(PTHLH):c.2T>G (p.Met1Arg)	Likely pathogenic
521834	NM_198965.2(PTHLH):c.524+2T>C	Likely pathogenic

SpliceAI

619 predictions. Top by Δscore:

Variant	Effect	Δscore
12:27963771:C:CC	acceptor_gain	1.0000
12:27963773:T:C	acceptor_gain	1.0000
12:27963786:T:TC	acceptor_gain	1.0000
12:27969387:CACTT:C	donor_loss	1.0000
12:27969388:ACTTA:A	donor_loss	1.0000
12:27969389:CTTA:C	donor_loss	1.0000
12:27969390:TTAC:T	donor_loss	1.0000
12:27969391:TA:T	donor_loss	1.0000
12:27969392:A:AC	donor_gain	1.0000
12:27969392:A:C	donor_loss	1.0000
12:27969392:ACAGG:A	donor_gain	1.0000
12:27969393:C:CA	donor_gain	1.0000
12:27969393:C:G	donor_loss	1.0000
12:27969393:CA:C	donor_gain	1.0000
12:27969393:CAG:C	donor_gain	1.0000
12:27969393:CAGG:C	donor_gain	1.0000
12:27969393:CAGGC:C	donor_gain	1.0000
12:27969512:GGGAC:G	acceptor_gain	1.0000
12:27969513:GGAC:G	acceptor_gain	1.0000
12:27969514:GAC:G	acceptor_gain	1.0000
12:27969515:AC:A	acceptor_gain	1.0000
12:27969516:CC:C	acceptor_gain	1.0000
12:27969517:C:CC	acceptor_gain	1.0000
12:27969517:CTG:C	acceptor_loss	1.0000
12:27969521:A:T	acceptor_gain	1.0000
12:27969523:C:CT	acceptor_gain	1.0000
12:27969524:A:T	acceptor_gain	1.0000
12:27970026:T:TA	donor_gain	1.0000
12:27963766:TTTTG:T	acceptor_gain	0.9900
12:27963768:TTG:T	acceptor_gain	0.9900

AlphaMissense

1131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:27963684:A:G	L63P	0.999
12:27963705:C:G	R56P	0.997
12:27963735:T:A	D46V	0.997
12:27963735:T:G	D46A	0.997
12:27963693:A:G	L60P	0.996
12:27963731:C:A	K47N	0.996
12:27963731:C:G	K47N	0.996
12:27963693:A:T	L60H	0.995
12:27963702:C:G	R57P	0.995
12:27963735:T:C	D46G	0.995
12:27963744:A:G	L43P	0.995
12:27963666:G:A	T69I	0.994
12:27963730:C:G	G48R	0.994
12:27963730:C:T	G48R	0.994
12:27963739:G:C	H45D	0.994
12:27963672:A:C	I67S	0.993
12:27963730:C:A	G48W	0.993
12:27963736:C:G	D46H	0.993
12:27963764:T:A	R36S	0.993
12:27963764:T:G	R36S	0.993
12:27963672:A:G	I67T	0.992
12:27963681:A:T	I64N	0.992
12:27963695:G:C	F59L	0.992
12:27963695:G:T	F59L	0.992
12:27963697:A:G	F59L	0.992
12:27963708:C:G	R55P	0.992
12:27963741:A:G	L44P	0.992
12:27963696:A:G	F59S	0.991
12:27963738:T:G	H45P	0.991
12:27963746:C:A	Q42H	0.991

dbSNP variants (sampled 300 via entrez): RS1000158666 (12:27969097 T>C), RS1000606041 (12:27966624 A>C), RS1000669163 (12:27972757 A>C,G), RS1000726240 (12:27961406 T>C), RS1001124085 (12:27972368 T>C), RS1001222125 (12:27961129 C>T), RS1001956253 (12:27960016 T>A,G), RS1001976949 (12:27974500 G>A), RS1002034975 (12:27960548 T>A), RS1002040957 (12:27968803 C>T), RS1002093220 (12:27968461 A>G), RS1002385757 (12:27960730 A>T), RS1002537761 (12:27973045 G>A,T), RS1002980434 (12:27959260 C>T), RS1003036062 (12:27958924 T>C)

Disease associations

OMIM: gene MIM:168470 | disease phenotypes: MIM:613382

GenCC curated gene-disease

Disease	Classification	Inheritance
brachydactyly type E2	Definitive	Autosomal dominant
brachydactyly type E	Supportive	Autosomal dominant

Mondo (2): brachydactyly type E2 (MONDO:0013244), brachydactyly type E (MONDO:0019677)

Orphanet (1): Brachydactyly type E (Orphanet:93387)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000677	Oligodontia
HP:0000684	Delayed eruption of teeth
HP:0001156	Brachydactyly
HP:0001382	Joint hypermobility
HP:0002007	Frontal bossing
HP:0004322	Short stature
HP:0005863	Type E brachydactyly
HP:0009882	Short distal phalanx of finger
HP:0010049	Short metacarpal
HP:0010076	Aplasia/Hypoplasia of the distal phalanx of the hallux
HP:0010743	Short metatarsal
HP:0100560	Upper limb asymmetry

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001585_2	Breast size	1.000000e-08
GCST001930_5	Breast cancer	2.000000e-12
GCST001937_58	Breast cancer	8.000000e-31
GCST002305_5	Breast cancer (estrogen-receptor negative, progesterone-receptor negative, and human epidermal growth factor-receptor negative)	2.000000e-08
GCST002322_12	Asthma and hay fever	3.000000e-07
GCST002492_2	Bone mineral density (paediatric, lower limb)	3.000000e-08
GCST002492_7	Bone mineral density (paediatric, lower limb)	1.000000e-07
GCST002494_12	Bone mineral density (paediatric, total body less head)	4.000000e-07
GCST002494_5	Bone mineral density (paediatric, total body less head)	4.000000e-08
GCST002545_5	Ossification of the posterior longitudinal ligament of the spine	4.000000e-12
GCST003842_13	Breast cancer (estrogen-receptor negative)	1.000000e-14
GCST003842_14	Breast cancer (estrogen-receptor negative)	4.000000e-13
GCST003845_14	Breast cancer	3.000000e-20
GCST003845_15	Breast cancer	7.000000e-18
GCST003985_3	Breast size	1.000000e-12
GCST006585_2478	Blood protein levels	7.000000e-07
GCST006661_325	Male-pattern baldness	1.000000e-08
GCST007014_10	Lumbar spine bone mineral density (trabecular)	2.000000e-06
GCST007091_22	Osteoarthritis (hip)	1.000000e-24
GCST008480_8	Lung function (FEV1)	1.000000e-13
GCST008482_6	Lung function (FVC)	1.000000e-17
GCST008839_339	Height	7.000000e-22
GCST009665_7	Breast cancer	3.000000e-10
GCST012353_31	Serum metabolite concentrations in chronic kidney disease	5.000000e-11
GCST90011770_61	Glaucoma (primary open-angle)	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007620	volumetric bone mineral density
EFO:0004314	forced expiratory volume
EFO:0004312	vital capacity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712869 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

89 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Zoledronic Acid	affects response to substance, decreases expression	3
Calcitriol	decreases expression, increases reaction, decreases stability, increases degradation, decreases reaction	3
Estradiol	decreases expression, affects cotreatment, increases expression, increases secretion	3
Progesterone	affects cotreatment, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment, increases expression	2
seocalcitol	decreases expression	2
chloropicrin	affects expression, decreases expression	2
Acrolein	affects cotreatment, increases expression, decreases expression, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
Arsenic	affects cotreatment, increases expression, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Dexamethasone	decreases expression	2
Dust	decreases expression	2
Ozone	affects cotreatment, increases expression, decreases expression, increases abundance	2
Tamoxifen	affects expression, increases secretion	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression	2
aminomethylphosphonic acid (AMPA)	increases expression	1
geldanamycin	affects cotreatment, decreases expression, increases expression	1
urushiol	increases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7DH	Abcam A-549 PTHLH KO	Cancer cell line	Male
CVCL_C7E7	Abcam HCT 116 PTHLH KO	Cancer cell line	Male

Clinical trials (associated diseases)

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