PLOD3

Summary

PLOD3 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 3, HGNC:9083) is a protein-coding gene on chromosome 7q22.1, encoding Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 (O60568). Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen.

The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VIB have deficiencies in lysyl hydroxylase activity.

Source: NCBI Gene 8985 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bone fragility with contractures, arterial rupture, and deafness (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 781 total — 21 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001084

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9083
Approved symbol	PLOD3
Name	procollagen-lysine,2-oxoglutarate 5-dioxygenase 3
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	LH3
Ensembl gene	ENSG00000106397
Ensembl biotype	protein_coding
OMIM	603066
Entrez	8985

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 13 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay

ENST00000223127, ENST00000414785, ENST00000421736, ENST00000424135, ENST00000440925, ENST00000454310, ENST00000456079, ENST00000460132, ENST00000460475, ENST00000463479, ENST00000466881, ENST00000478082, ENST00000478264, ENST00000481461, ENST00000487563, ENST00000489927, ENST00000890269, ENST00000890270, ENST00000890271, ENST00000890272, ENST00000890273, ENST00000890274, ENST00000890275, ENST00000890276

RefSeq mRNA: 1 — MANE Select: NM_001084 NM_001084

CCDS: CCDS5715

Canonical transcript exons

ENST00000223127 — 19 exons

Exon	Start	End
ENSE00000712224	101206779	101206904
ENSE00000712229	101207578	101207724
ENSE00000712233	101208853	101208957
ENSE00000712236	101210093	101210161
ENSE00001055540	101217166	101217581
ENSE00001770192	101211591	101211716
ENSE00003459144	101215089	101215152
ENSE00003459705	101210331	101210444
ENSE00003465045	101210532	101210673
ENSE00003506928	101212842	101212943
ENSE00003521405	101213107	101213204
ENSE00003540185	101216410	101216546
ENSE00003561774	101212530	101212655
ENSE00003630020	101216695	101216786
ENSE00003632106	101215908	101216020
ENSE00003678297	101211846	101211950
ENSE00003685860	101212253	101212374
ENSE00003787674	101216163	101216326
ENSE00003850080	101205984	101206436

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.9917 / max 347.4721, expressed in 1823 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85319	32.5736	1817
85315	11.9485	1701
85317	6.0474	1608
85316	0.3645	184
85318	0.3493	147
204616	0.3339	153
85313	0.1875	66
85314	0.0971	23
85312	0.0901	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	98.24	gold quality
pancreatic ductal cell	CL:0002079	97.35	gold quality
tibial nerve	UBERON:0001323	95.52	gold quality
mucosa of transverse colon	UBERON:0004991	95.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.15	gold quality
endometrium epithelium	UBERON:0004811	95.06	gold quality
omental fat pad	UBERON:0010414	94.16	gold quality
peritoneum	UBERON:0002358	94.12	gold quality
spinal cord	UBERON:0002240	94.11	gold quality
body of uterus	UBERON:0009853	94.11	gold quality
granulocyte	CL:0000094	94.05	gold quality
transverse colon	UBERON:0001157	93.92	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.86	gold quality
lower esophagus	UBERON:0013473	93.84	gold quality
upper lobe of left lung	UBERON:0008952	93.80	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.76	gold quality
right lobe of liver	UBERON:0001114	93.66	gold quality
apex of heart	UBERON:0002098	93.62	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.62	gold quality
sural nerve	UBERON:0015488	93.50	gold quality
ileal mucosa	UBERON:0000331	93.46	gold quality
left coronary artery	UBERON:0001626	93.46	gold quality
left uterine tube	UBERON:0001303	93.40	gold quality
upper lobe of lung	UBERON:0008948	93.33	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.31	gold quality
metanephros cortex	UBERON:0010533	93.10	gold quality
endocervix	UBERON:0000458	93.07	gold quality
decidua	UBERON:0002450	93.07	gold quality
right atrium auricular region	UBERON:0006631	93.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.46
E-CURD-53	no	252.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting PLOD3, 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-548AN	99.97	70.91	2817
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-759	96.16	66.77	873
HSA-MIR-3186-3P	82.87	62.46	32

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• Characterization of three fragments that constitute the monomers of the human lysyl hydroxylase isoenzymes 1-3. The 30-kDa N-terminal fragment is not required for lysyl hydroxylase activity (PMID:11956192)
• Manipulation of the gene for LH3 can be used to selectively alter glycosylation and hydroxylation reactions, and provides new tool to clarify functions of unique hydroxylysine linked carbohydrates in collagens and other proteins. (PMID:12475640)
• LH3 is present and active in the extracellular space (PMID:16447251)
• The deficiency of LH3 glycosyltransferase activities, especially in the extracellular space, causes growth arrest. (PMID:18298658)
• mutations of the lysyl hydroxylase 3 gene may cause a connective tissue disorder [case report] (PMID:18834968)
• Dimerization of human lysyl hydroxylase 3 is mediated by the amino acids 541-547 (PMID:20955792)
• LH3 molecules found in the cell medium are secreted through the Golgi complex, and the secretion is dependent on LH3 glycosyltransferase activity; LH3 found on the cell surface bypasses the Golgi complex (PMID:21465473)
• MMP-9 recruitment to the fibroblast cell surface by Lysyl Hydroxylase 3 (LH3) triggers TGF-beta activation and fibroblast differentiation (PMID:25825495)
• The study shows that lysyl hydroxylase 3 localizes to epidermal basement membrane and is reduced in patients with recessive dystrophic epidermolysis bullosa. (PMID:26380979)
• Proteomic analysis revealed that PLOD3, which is the gene encoding for collagen-modifying lysyl hydroxylase 3 (LH3), is regulated by miR-663a. (PMID:27233793)
• VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers (PMID:27435297)
• These results indicate that PLOD3 promotes lung cancer metastasis in a RAS-MAP kinase pathway-independent manner. Therefore, secreted PLOD3 serves as a potent inducer of lung cancer metastasis and a potential therapeutic target to enhance survival in lung cancer. (PMID:30442941)
• PLOD3 siRNA suppresses radioresistance and chemoresistance by inducing apoptosis and renders PLOD3 as a candidate lung cancer biomarker. (PMID:30770789)
• Results indicate that procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3) may promote the progression of gastric cancer (GC). (PMID:30775879)
• These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes. (PMID:31129566)
• our results demonstrate the novel function of the collagen-like glycosylation of CCN1 and suggest that lysyl hydroxylase3-mediated glycosylation is important for CCN1 secretion. (PMID:31317175)
• Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma. (PMID:31446433)
• Knockdown of PLOD3 suppresses the malignant progression of renal cell carcinoma via reducing TWIST1 expression. (PMID:32585183)
• PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43. (PMID:33483598)
• COLGALT2 is overexpressed in ovarian cancer and interacts with PLOD3. (PMID:33783989)
• Polypeptide N-acetylgalactosaminyltransferase 18 retains in endoplasmic reticulum depending on its luminal regions interacting with ER resident UGGT1, PLOD3 and LPCAT1. (PMID:33909026)
• Involvement of LH3 and GLT25D1 for glucosyl-galactosyl-hydroxylation on non-collagen-like domain of FGL1. (PMID:33984770)
• PLOD3 Is Associated with Immune Cell Infiltration and Genomic Instability in Colon Adenocarcinoma. (PMID:34239923)
• Characterization of a cancer-associated Epstein-Barr virus EBNA1 variant reveals a novel interaction with PLOD1 and PLOD3. (PMID:34304093)
• A Human Pan-Cancer System Analysis of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 3 (PLOD3). (PMID:34576068)
• Integrated Profiling Identifies PLOD3 as a Potential Prognostic and Immunotherapy Relevant Biomarker in Colorectal Cancer. (PMID:34646265)
• PLOD3 regulates the expression of YAP1 to affect the progression of non-small cell lung cancer via the PKCdelta/CDK1/LIMD1 signaling pathway. (PMID:35039611)
• Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen alpha1alpha1alpha2(IV). (PMID:36403858)
• PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-alpha/ NF-kappaB pathway. (PMID:38184566)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plod3	ENSDARG00000076317
mus_musculus	Plod3	ENSMUSG00000004846
rattus_norvegicus	Plod3	ENSRNOG00000001417
drosophila_melanogaster	Plod	FBGN0036147
caenorhabditis_elegans		WBGENE00002497

Paralogs (5): PLOD1 (ENSG00000083444), COLGALT1 (ENSG00000130309), PLOD2 (ENSG00000152952), CERCAM (ENSG00000167123), COLGALT2 (ENSG00000198756)

Protein

Protein identifiers

Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3 — O60568 (reviewed: O60568)

All UniProt accessions (7): O60568, C9JIX5, C9JU11, H7C0B8, H7C2A8, H7C2S8, H7C2V1

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen. Plays a redundant role in catalyzing the formation of hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. Plays a redundant role in catalyzing the transfer of galactose onto hydroxylysine groups, giving rise to galactosyl 5-hydroxylysine. Has an essential role by catalyzing the subsequent transfer of glucose moieties, giving rise to 1,2-glucosylgalactosyl-5-hydroxylysine residues. Catalyzes hydroxylation and glycosylation of Lys residues in the MBL1 collagen-like domain, giving rise to hydroxylysine and 1,2-glucosylgalactosyl-5-hydroxylysine residues. Essential for normal biosynthesis and secretion of type IV collagens. Essential for normal formation of basement membranes.

Subunit / interactions. Homodimer.

Subcellular location. Rough endoplasmic reticulum. Endoplasmic reticulum lumen. Endoplasmic reticulum membrane. Secreted. Extracellular space.

Tissue specificity. Ubiquitous. Detected in heart, placenta and pancreas and at lower levels in lung, liver and skeletal muscle.

Disease relevance. BCARD syndrome (BCARD) [MIM:612394] An autosomal recessive connective tissue disorder, secondary to lysyl hydroxylase 3 deficiency. It is characterized by congenital malformations severely affecting multiple tissues and organs. Clinical features include growth retardation, craniofacial dysmorphism, popliteal and cerebral aneurysm, cerebral arterial hemorrhage, skin blistering and easy bruisability, and osteopenia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Lysyl hydroxylase activity is strongly inhibited by imidazole.

Domain organisation. The N-terminal domain mediates glycosyltransferase activity. The C-terminal domain that mediates lysyl hydroxylase activity is also important for homodimerization.

RefSeq proteins (1): NP_001075* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001006	Procol_lys_dOase	Conserved_site
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR006620	Pro_4_hyd_alph	Domain
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily
IPR044861	IPNS-like_FE2OG_OXY	Domain
IPR050757	Collagen_mod_GT25	Family
IPR057589	GT_PLOD	Domain

Pfam: PF03171, PF25342

Enzyme classification (BRENDA):

• EC 1.14.11.4 — procollagen-lysine 5-dioxygenase (BRENDA: 11 organisms, 68 substrates, 38 inhibitors, 43 Km, 4 kcat entries)
• EC 2.4.1.50 — procollagen galactosyltransferase (BRENDA: 7 organisms, 62 substrates, 25 inhibitors, 19 Km, 0 kcat entries)
• EC 2.4.1.66 — procollagen glucosyltransferase (BRENDA: 8 organisms, 97 substrates, 35 inhibitors, 28 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.011–0.25	8
UDP-GLUCOSE	0.005–0.15	8
(ILE-LYS-GLY)3	0.31–0.8	6
ASCORBATE	0.05–0.35	5
COLLAGEN	0.167–0.63	4
D-GALACTOSYLHYDROXYLYSINE	0.002–3.8	4
(IKG)3	0.4–5	3
ALA-ARG-GLY-ILE-LYS-GLY-ILE-ARG-GLY-PHE-SER-GLY	0.4–0.6	3
TYPE I PROCOLLAGEN	0.08–0.23	3
TYPE IV PROCOLLAGEN	0.04–0.3	3
COLLAGEN	0.0008–0.0072	2
UDP-GALACTOSE	0.0188–0.0335	2
UDPGALACTOSE	0.03–0.049	2
(L-ILE-L-LYS-GLY)3	0.43	1
(PRO-PRO-GLY)4-ALA-ARG-GLY-MET-LYS-GLY-HIS-ARG-G	0.2	1

Catalyzed reactions (Rhea), 3 shown:

• (5R)-5-O-(beta-D-galactosyl)-5-hydroxy-L-lysyl-[collagen] + UDP-alpha-D-glucose = (5R)-5-O-[alpha-D-glucosyl-(1->2)-beta-D-galactosyl]-5-hydroxy-L-lysyl-[collagen] + UDP + H(+) (RHEA:12576)
• (5R)-5-hydroxy-L-lysyl-[collagen] + UDP-alpha-D-galactose = (5R)-5-O-(beta-D-galactosyl)-5-hydroxy-L-lysyl-[collagen] + UDP + H(+) (RHEA:12637)
• L-lysyl-[collagen] + 2-oxoglutarate + O2 = (5R)-5-hydroxy-L-lysyl-[collagen] + succinate + CO2 (RHEA:16569)

UniProt features (124 total): strand 48, helix 30, binding site 13, mutagenesis site 11, turn 7, sequence variant 4, disulfide bond 3, region of interest 3, glycosylation site 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
6WFV	X-RAY DIFFRACTION	1.7
6FXM	X-RAY DIFFRACTION	2.1
6FXR	X-RAY DIFFRACTION	2.1
6FXY	X-RAY DIFFRACTION	2.14
6TES	X-RAY DIFFRACTION	2.2
6TE3	X-RAY DIFFRACTION	2.3
6TEX	X-RAY DIFFRACTION	2.3
8ONE	X-RAY DIFFRACTION	2.3
6TEC	X-RAY DIFFRACTION	2.4
6FXT	X-RAY DIFFRACTION	2.5
6FXK	X-RAY DIFFRACTION	2.7
6TEZ	X-RAY DIFFRACTION	2.7
6FXX	X-RAY DIFFRACTION	3
6TEU	X-RAY DIFFRACTION	3
8ZGE	ELECTRON MICROSCOPY	3.4
8ZGC	ELECTRON MICROSCOPY	3.58
8ZGG	ELECTRON MICROSCOPY	3.75
8ZGH	ELECTRON MICROSCOPY	3.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60568-F1	91.80	0.84

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 (13): 253; 256–259; 599; 656; 667; 669; 676; 719; 729; 44–46; 112–114; 112 …

Disulfide bonds (3): 279–282, 379–385, 563–698

Glycosylation sites (2): 63, 548

Mutagenesis-validated functional residues (11):

Position	Phenotype
75	decreased lysyl hydroxylase activity and loss of glycosyltransferase activity.
114	decreased lysyl hydroxylase and glycosyltransferase activity.
144	strongly reduced glucosyltransferase activity. strongly reduced galactosyltransferase activity.
187–191	loss of glucosyltransferase activity. loss of galactosyltransferase activity.
187–189	nearly abolishes glucosyltransferase activity. nearly abolishes galactosyltransferase activity.
208	reduced glucosyltransferase activity.
669	strongly decreased lysyl hydroxylase activity. no effect on glycosyltransferase activity.
672	loss of dimerization. loss of lysyl hydroxylase activity and decreased glycosyltransferase activity.
714	loss of dimerization. loss of lysyl hydroxylase activity and no effect on glycosyltransferase activity.
715	no effect on dimerization, lysyl hydroxylase and glycosyltransferase activity.
715	loss of lysyl hydroxylase activity and decreased glycosyltransferase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes

MSigDB gene sets: 388 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, MODULE_93, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_LUNG_MORPHOGENESIS

GO Biological Process (15): in utero embryonic development (GO:0001701), endothelial cell morphogenesis (GO:0001886), intracellular protein localization (GO:0008104), neural tube development (GO:0021915), collagen fibril organization (GO:0030199), collagen biosynthetic process (GO:0032964), vasodilation (GO:0042311), obsolete hydroxylysine biosynthetic process (GO:0046947), epidermis morphogenesis (GO:0048730), lung morphogenesis (GO:0060425), basement membrane assembly (GO:0070831), protein O-linked glycosylation via galactose (GO:0180062), protein O-linked glycosylation (GO:0006493), peptidyl-lysine hydroxylation (GO:0017185), collagen metabolic process (GO:0032963)

GO Molecular Function (14): iron ion binding (GO:0005506), procollagen-lysine 5-dioxygenase activity (GO:0008475), L-ascorbic acid binding (GO:0031418), procollagen glucosyltransferase activity (GO:0033823), small molecule binding (GO:0036094), metal ion binding (GO:0046872), procollagen galactosyltransferase activity (GO:0050211), catalytic activity (GO:0003824), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757), dioxygenase activity (GO:0051213)

GO Cellular Component (11): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), rough endoplasmic reticulum (GO:0005791), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
catalytic activity, acting on a protein	3
chordate embryonic development	2
binding	2
catalytic activity	2
oxidoreductase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
endoplasmic reticulum	2
cellular anatomical structure	2
endothelial cell development	1
epithelial cell morphogenesis	1
macromolecule localization	1
nervous system development	1
tube development	1
epithelium development	1
extracellular matrix organization	1
biosynthetic process	1
collagen metabolic process	1
blood vessel diameter maintenance	1
morphogenesis of an epithelium	1
epidermis development	1
animal organ morphogenesis	1
lung development	1
basement membrane organization	1
extracellular matrix assembly	1
protein O-linked glycosylation	1
glycoprotein biosynthetic process	1
protein hydroxylation	1
peptidyl-lysine modification	1
metabolic process	1
transition metal ion binding	1
2-oxoglutarate-dependent dioxygenase activity	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
glucosyltransferase activity	1
cation binding	1
UDP-galactosyltransferase activity	1

Protein interactions and networks

STRING

978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLOD3	CHST14	Q8NCH0	713
PLOD3	P4HA1	P13674	671
PLOD3	ZNF469	Q96JG9	671
PLOD3	P4HA2	O15460	638
PLOD3	COL4A1	P02462	526
PLOD3	MMP9	P14780	474
PLOD3	P3H1	Q32P28	470
PLOD3	COL17A1	Q9UMD9	459
PLOD3	P4HA3	Q7Z4N8	449
PLOD3	P3H4	Q92791	423
PLOD3	GALNT18	Q6P9A2	414
PLOD3	NOMO2	Q5JPE7	397
PLOD3	LOXL1	Q08397	396
PLOD3	COLGALT1	Q8NBJ5	388
PLOD3	LOX	P28300	384

IntAct

150 interactions, top by confidence:

A	B	Type	Score
PLOD3	EFHC2	psi-mi:“MI:0915”(physical association)	0.890
EFHC2	PLOD3	psi-mi:“MI:0915”(physical association)	0.890
PLOD3	EHMT2	psi-mi:“MI:0915”(physical association)	0.830
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
PLOD3	RAB3IP	psi-mi:“MI:0915”(physical association)	0.670
RAB3IP	PLOD3	psi-mi:“MI:0915”(physical association)	0.670
PLOD3	EHMT2	psi-mi:“MI:0915”(physical association)	0.560
EHMT2	PLOD3	psi-mi:“MI:0915”(physical association)	0.560
PLOD3	RAB3IP	psi-mi:“MI:0915”(physical association)	0.560
PLOD3	ZNF620	psi-mi:“MI:0915”(physical association)	0.560
PLOD3	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.560
PLOD3	NAB2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (204): EHMT2 (Two-hybrid), EFHC2 (Two-hybrid), RAB3IP (Two-hybrid), CCDC85B (Two-hybrid), RHOXF2 (Two-hybrid), FAM153A (Two-hybrid), EHMT2 (Two-hybrid), DPPA2 (Two-hybrid), RHOXF2 (Affinity Capture-Western), PLOD3 (Co-fractionation), POR (Co-fractionation), PLOD3 (Affinity Capture-MS), PLOD3 (Proximity Label-MS), PLOD3 (Proximity Label-MS), PLOD3 (Two-hybrid)

ESM2 similar proteins: A4IID1, A5D7I4, A5PK45, A9X1C8, G5E897, O12971, O60568, O77783, O95803, P52848, P52849, P52850, P70428, P97464, Q02353, Q16394, Q3UHN9, Q5F407, Q5IGR6, Q5IGR7, Q5IGR8, Q5M854, Q5R6K5, Q5RBC3, Q5U367, Q5U4X8, Q6EV56, Q6GMK0, Q6GQI7, Q6GQK9, Q6IS24, Q6UW63, Q6ZQ11, Q7TT15, Q7Z4H8, Q812F8, Q86X52, Q8K297, Q8NBJ5, Q8VHI3

Diamond homologs: A5PMF6, O00469, O60568, O77588, P24802, Q02809, Q20679, Q5R6K5, Q5R9N3, Q5U367, Q5U483, Q63321, Q811A3, Q8NBJ5, Q9R0B9, Q9R0E1, Q9R0E2, Q9VTH0, Q5U309, Q8IYK4, A0JPH3, Q5UQC3, Q6NVG7, Q8K297, A5PK45, Q6N063, Q7Q021, A3KGW5, A7MB73, P57033, P71398, Q17FB8, Q29NU5, Q50947, Q51116, Q5T4B2, Q5UQ62, Q8IPK4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 116 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Collagen chain trimerization	7	25.2×	2e-06
Collagen biosynthesis and modifying enzymes	10	23.7×	4e-09
Collagen degradation	7	17.1×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to amino acid stimulus	6	18.9×	7e-04
autophagosome maturation	5	18.1×	4e-03
collagen fibril organization	5	11.6×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	15
Uncertain significance	280
Likely benign	359
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1424180	NM_001084.5(PLOD3):c.889dup (p.Arg297fs)	Pathogenic
1428705	NM_001084.5(PLOD3):c.876dup (p.Gln293fs)	Pathogenic
1428774	NM_001084.5(PLOD3):c.244C>T (p.Arg82Ter)	Pathogenic
1686083	NM_001084.5(PLOD3):c.2061+1G>A	Pathogenic
1898291	NM_001084.5(PLOD3):c.946C>T (p.Gln316Ter)	Pathogenic
1934934	NM_001084.5(PLOD3):c.1869G>A (p.Trp623Ter)	Pathogenic
2035674	NM_001084.5(PLOD3):c.1858G>T (p.Glu620Ter)	Pathogenic
2159445	NM_001084.5(PLOD3):c.1354C>T (p.Arg452Ter)	Pathogenic
2693153	NM_001084.5(PLOD3):c.865del (p.Leu289fs)	Pathogenic
2705859	NM_001084.5(PLOD3):c.59del (p.Pro20fs)	Pathogenic
2783463	NM_001084.5(PLOD3):c.53_65dup (p.Ser23fs)	Pathogenic
2787301	NM_001084.5(PLOD3):c.1289dup (p.Ala431fs)	Pathogenic
2859808	NM_001084.5(PLOD3):c.131_132del (p.Val44fs)	Pathogenic
2984840	NM_001084.5(PLOD3):c.889del (p.Arg297fs)	Pathogenic
3245863	NC_000007.13:g.(?100860427)(100860555_?)del	Pathogenic
3619972	NC_000007.14:g.101216785CT[1]	Pathogenic
3694254	NM_001084.5(PLOD3):c.1036dup (p.Ser346fs)	Pathogenic
4704492	NM_001084.5(PLOD3):c.485_486del (p.Arg162fs)	Pathogenic
4763903	NM_001084.5(PLOD3):c.1909_1910dup (p.Ser637fs)	Pathogenic
4782269	NM_001084.5(PLOD3):c.1492C>T (p.Arg498Ter)	Pathogenic
6644	NM_001084.5(PLOD3):c.2071del (p.Cys691fs)	Pathogenic
1700176	NM_001084.5(PLOD3):c.209G>A (p.Gly70Asp)	Likely pathogenic
1939669	NM_001084.5(PLOD3):c.1935+1G>A	Likely pathogenic
2023516	NM_001084.5(PLOD3):c.202-1G>T	Likely pathogenic
2763722	NM_001084.5(PLOD3):c.880-2A>C	Likely pathogenic
2796567	NM_001084.5(PLOD3):c.1006-1_1006delinsCA	Likely pathogenic
2806148	NM_001084.5(PLOD3):c.503-2A>G	Likely pathogenic
2897011	NM_001084.5(PLOD3):c.1005+1G>A	Likely pathogenic
3065547	NM_001084.5(PLOD3):c.1359-1G>C	Likely pathogenic
3669517	NM_001084.5(PLOD3):c.1614+1G>T	Likely pathogenic

SpliceAI

3239 predictions. Top by Δscore:

Variant	Effect	Δscore
7:101206433:CTCC:C	acceptor_gain	1.0000
7:101206434:TCC:T	acceptor_gain	1.0000
7:101206435:CC:C	acceptor_gain	1.0000
7:101206435:CCC:C	acceptor_gain	1.0000
7:101206436:CC:C	acceptor_gain	1.0000
7:101206436:CCT:C	acceptor_loss	1.0000
7:101206437:C:CC	acceptor_gain	1.0000
7:101206437:C:CG	acceptor_loss	1.0000
7:101206438:T:A	acceptor_loss	1.0000
7:101206774:CGCA:C	donor_loss	1.0000
7:101206775:GCAC:G	donor_loss	1.0000
7:101206776:CACCT:C	donor_loss	1.0000
7:101206900:CGCGC:C	acceptor_gain	1.0000
7:101206901:GCGC:G	acceptor_gain	1.0000
7:101206902:CGC:C	acceptor_gain	1.0000
7:101206902:CGCC:C	acceptor_gain	1.0000
7:101206903:GC:G	acceptor_gain	1.0000
7:101206903:GCCTG:G	acceptor_loss	1.0000
7:101206904:CC:C	acceptor_gain	1.0000
7:101206905:C:CC	acceptor_gain	1.0000
7:101207572:GCGCA:G	donor_loss	1.0000
7:101207573:CGCAC:C	donor_loss	1.0000
7:101207574:GCACC:G	donor_loss	1.0000
7:101207575:CACCT:C	donor_loss	1.0000
7:101207576:A:C	donor_loss	1.0000
7:101207577:C:CA	donor_loss	1.0000
7:101208847:CCTTA:C	donor_loss	1.0000
7:101208848:CTTA:C	donor_loss	1.0000
7:101208849:TTACC:T	donor_loss	1.0000
7:101208850:TACCT:T	donor_loss	1.0000

AlphaMissense

4801 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:101206293:A:C	F735L	1.000
7:101206293:A:T	F735L	1.000
7:101206295:A:G	F735L	1.000
7:101206343:G:C	H719D	1.000
7:101206834:T:A	D669V	1.000
7:101206834:T:G	D669A	1.000
7:101206841:G:C	H667D	1.000
7:101206884:A:C	F652L	1.000
7:101206884:A:T	F652L	1.000
7:101206886:A:G	F652L	1.000
7:101208871:C:A	W590C	1.000
7:101208871:C:G	W590C	1.000
7:101211662:C:A	W429C	1.000
7:101211662:C:G	W429C	1.000
7:101211664:A:G	W429R	1.000
7:101211664:A:T	W429R	1.000
7:101206294:A:C	F735C	0.999
7:101206343:G:T	H719N	0.999
7:101206360:C:T	G713D	0.999
7:101206367:G:C	H711D	0.999
7:101206420:A:G	F693S	0.999
7:101206800:G:C	N680K	0.999
7:101206800:G:T	N680K	0.999
7:101206804:A:T	L679H	0.999
7:101206828:G:A	S671F	0.999
7:101206828:G:T	S671Y	0.999
7:101206829:A:G	S671P	0.999
7:101206833:G:C	D669E	0.999
7:101206833:G:T	D669E	0.999
7:101206834:T:C	D669G	0.999

dbSNP variants (sampled 300 via entrez): RS1000051178 (7:101215081 C>T), RS1000275756 (7:101210342 C>T), RS1000878971 (7:101211114 C>T), RS1001060654 (7:101213707 T>C), RS1001112875 (7:101213484 T>G), RS1001154230 (7:101215931 G>A), RS1001414674 (7:101205564 T>A), RS1001458575 (7:101217056 G>A,C), RS1001684009 (7:101209128 T>C), RS1001843506 (7:101217963 G>A), RS1002288604 (7:101207950 T>A), RS1003116850 (7:101211411 G>A), RS1003250709 (7:101216942 G>A,T), RS1003453723 (7:101219473 C>G), RS1003680480 (7:101209759 T>C)

Disease associations

OMIM: gene MIM:603066 | disease phenotypes: MIM:612394, MIM:614519

GenCC curated gene-disease

Disease	Classification	Inheritance
bone fragility with contractures, arterial rupture, and deafness	Strong	Autosomal recessive

Mondo (3): bone fragility with contractures, arterial rupture, and deafness (MONDO:0012892), hemorrhage, intracerebral, susceptibility to (MONDO:0100533), congenital portosystemic shunt (MONDO:0018811)

Orphanet (2): Connective tissue disorder due to lysyl hydroxylase-3 deficiency (Orphanet:300284), Congenital portosystemic shunt (Orphanet:480531)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000272	Malar flattening
HP:0000307	Pointed chin
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000586	Shallow orbits
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000978	Bruising susceptibility
HP:0001263	Global developmental delay
HP:0001511	Intrauterine growth retardation
HP:0001776	Bilateral talipes equinovarus
HP:0001873	Thrombocytopenia
HP:0002119	Ventriculomegaly
HP:0002132	Porencephalic cyst
HP:0002164	Nail dysplasia
HP:0002208	Coarse hair
HP:0002650	Scoliosis
HP:0002680	J-shaped sella turcica
HP:0002714	Downturned corners of mouth
HP:0002756	Pathologic fracture
HP:0002987	Elbow flexion contracture
HP:0003090	Hypoplasia of the capital femoral epiphysis
HP:0003196	Short nose
HP:0003393	Thenar muscle atrophy
HP:0003645	Prolonged partial thromboplastin time

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_626	Blood protein levels	7.000000e-06
GCST012481_4	Cerebral amyloid angiopathy in Alzheimer’s disease	6.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567320	Bone Fragility with Contractures, Arterial Rupture, and Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465277 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.57	IC50	2700	nM	CHEMBL5433830
5.33	IC50	4700	nM	CHEMBL5422717
5.32	IC50	4800	nM	CHEMBL5401981
5.32	IC50	4800	nM	CHEMBL5431602
5.28	IC50	5200	nM	CHEMBL1089782
5.28	IC50	5200	nM	CHEMBL1443628

PubChem BioAssay actives

6 with measured affinity, of 6 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-(3-morpholin-4-ylphenyl)-3-pyridin-4-ylpropane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	2.7000	uM
1-[3-(4-methylpiperazin-1-yl)phenyl]-3-pyridin-4-ylpropane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	4.7000	uM
1-(3-morpholin-4-ylphenyl)-3-pyridin-3-ylpropane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	4.8000	uM
4,4,4-trifluoro-1-pyridin-4-ylbutane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	4.8000	uM
1-phenyl-3-pyridin-4-ylpropane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	5.2000	uM
4,4,4-trifluoro-1-pyridin-3-ylbutane-1,3-dione	2016723: Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	5.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects cotreatment, increases methylation, decreases expression, increases expression	5
Cyclosporine	decreases methylation, increases expression	3
epigallocatechin gallate	increases expression, affects cotreatment	2
Acetaminophen	decreases expression, affects response to substance	2
Doxorubicin	affects cotreatment, affects expression, decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	increases expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
tetrabromobisphenol A	increases expression	1
1,10-phenanthroline	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
puerarin	increases expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases expression	1
pomiferin	increases expression	1
osajin	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
rosavin	increases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Arsenic	affects 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
CHEMBL5370456	Binding	Inhibition of human recombinant LH3 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors. — ACS Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3E4	Abcam HEK293T PLOD3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension