PLOD1

Summary

PLOD1 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1, HGNC:9081) is a protein-coding gene on chromosome 1p36.22, encoding Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (Q02809). Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils.

Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the 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 VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5351 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Ehlers-Danlos syndrome, kyphoscoliotic type 1 (Definitive, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 1,434 total — 69 pathogenic, 50 likely-pathogenic
• Phenotypes (HPO): 97
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000302

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9081
Approved symbol	PLOD1
Name	procollagen-lysine,2-oxoglutarate 5-dioxygenase 1
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	LH1
Ensembl gene	ENSG00000083444
Ensembl biotype	protein_coding
OMIM	153454
Entrez	5351

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 25 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000196061, ENST00000358133, ENST00000429000, ENST00000449038, ENST00000465920, ENST00000470133, ENST00000481933, ENST00000485046, ENST00000491536, ENST00000854019, ENST00000854020, ENST00000854021, ENST00000854022, ENST00000854023, ENST00000854024, ENST00000854025, ENST00000854026, ENST00000854027, ENST00000854028, ENST00000854029, ENST00000854030, ENST00000854031, ENST00000854032, ENST00000854033, ENST00000934210, ENST00000934211, ENST00000934212, ENST00000934213, ENST00000934214, ENST00000960558, ENST00000960559

RefSeq mRNA: 2 — MANE Select: NM_000302 NM_000302, NM_001316320

CCDS: CCDS142

Canonical transcript exons

ENST00000196061 — 19 exons

Exon	Start	End
ENSE00000818966	11974653	11975537
ENSE00001561283	11934717	11934855
ENSE00001664074	11972872	11972997
ENSE00001665521	11960646	11960767
ENSE00001675950	11970670	11970816
ENSE00001720837	11964175	11964300
ENSE00001752126	11964644	11964785
ENSE00001762805	11963532	11963636
ENSE00001769527	11958516	11958647
ENSE00003464431	11966987	11967091
ENSE00003465125	11965480	11965593
ENSE00003526105	11956917	11957014
ENSE00003527107	11950357	11950520
ENSE00003530497	11954830	11954893
ENSE00003543011	11952623	11952735
ENSE00003625358	11947976	11948067
ENSE00003680837	11966251	11966316
ENSE00003680847	11949773	11949906
ENSE00003788182	11957842	11957943

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 100.9841 / max 1292.6320, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
653	100.0713	1820
663	0.9128	534

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.14	gold quality
smooth muscle tissue	UBERON:0001135	96.09	gold quality
apex of heart	UBERON:0002098	95.23	gold quality
ascending aorta	UBERON:0001496	94.99	gold quality
thoracic aorta	UBERON:0001515	94.89	gold quality
right lobe of liver	UBERON:0001114	94.83	gold quality
right ovary	UBERON:0002118	94.73	gold quality
right coronary artery	UBERON:0001625	94.64	gold quality
left uterine tube	UBERON:0001303	94.59	gold quality
right atrium auricular region	UBERON:0006631	94.39	gold quality
body of uterus	UBERON:0009853	94.38	gold quality
gall bladder	UBERON:0002110	94.29	gold quality
endocervix	UBERON:0000458	94.08	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.92	gold quality
lower esophagus	UBERON:0013473	93.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.89	gold quality
left coronary artery	UBERON:0001626	93.77	gold quality
coronary artery	UBERON:0001621	93.75	gold quality
descending thoracic aorta	UBERON:0002345	93.73	gold quality
omental fat pad	UBERON:0010414	93.63	gold quality
heart left ventricle	UBERON:0002084	93.62	gold quality
peritoneum	UBERON:0002358	93.61	gold quality
cardiac ventricle	UBERON:0002082	93.41	gold quality
left ovary	UBERON:0002119	93.18	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.97	gold quality
myometrium	UBERON:0001296	92.79	gold quality
heart	UBERON:0000948	92.75	gold quality
liver	UBERON:0002107	92.68	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	74.33
E-HCAD-13	yes	11.55
E-GEOD-84465	yes	5.82
E-MTAB-7303	no	877.11
E-MTAB-7037	no	509.79
E-MTAB-7051	no	384.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NKX2-5, PITX2

miRNA regulators (miRDB)

43 targeting PLOD1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-6862-3P	97.92	64.86	531

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• 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)
• Results indicate that a C-terminal 40 amino acid segment of lysyl hydroxylase confers endoplasmic reticulum residency in a KDEL-receptor-independent manner. (PMID:12452796)
• The results suggest that PLOD1 at 1p36, individually or in different combinations, contribute to osteoporosis susceptibility in Chinese. (PMID:19442614)
• Common polymorphisms in four candidate genes (COL11A1, COL18A1, FBN1 and PLOD1) were unlikely to play important roles in the genetic susceptibility to high myopia. (PMID:21527992)
• Data show that homozygous and compound heterozygous changes found in PLOD1 and SLC2A10 may confer autosomal recessive effects, and three MYH11, ACTA2 and COL3A1 heterozygous variants were considered as putative pathogenic gene alterations. (PMID:22001912)
• Compared to slow progressing Alzheimer’s disease, PLOD1 is upregulated in fast progressing Alzheimer’s disease ;patients. (PMID:23234877)
• Deficiency of the enzyme lysyl hydroxylase 1 (LH1) due to mutations in PLOD1 results in underhydroxylation of collagen lysyl residues and, hence, in the abnormal formation of collagen cross-links. (PMID:25277362)
• Ehlers Danlos syndrome in two children was confirmed by mutations in PLOD1 gene. Initially patients were thought to have either a diagnosis of classical EDS (cEDS) or a neuromuscular disorder due to absence of (congenital) scoliosis. (PMID:28757364)
• results indicated that PLOD1 is highly expressed in gastrointestinal carcinoma and is a potential prognostic marker and therapeutic target (PMID:29723071)
• the present study showed that PLOD1 may be a potential prognostic marker and therapeutic target for Bladder cancer. (PMID:31199049)
• Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma. (PMID:31446433)
• PLOD1, a target of miR-34c, contributes to cell growth and metastasis via repressing LATS1 phosphorylation and inactivating Hippo pathway in osteosarcoma. (PMID:32446383)
• PLOD1 Is a Prognostic Biomarker and Mediator of Proliferation and Invasion in Osteosarcoma. (PMID:33134376)
• Hypoxia-induced PLOD1 overexpression contributes to the malignant phenotype of glioblastoma via NF-kappaB signaling. (PMID:33420370)
• PLODs are overexpressed in ovarian cancer and are associated with gap junctions via connexin 43. (PMID:33483598)
• A floppy infant without lingual frenulum and kyphoscoliosis: Ehlers Danlos syndrome case report. (PMID:33579342)
• Characterization of a cancer-associated Epstein-Barr virus EBNA1 variant reveals a novel interaction with PLOD1 and PLOD3. (PMID:34304093)
• New mechanistic insights to PLOD1-mediated human vascular disease. (PMID:34400365)
• PLOD1 promotes cell growth and aerobic glycolysis by regulating the SOX9/PI3K/Akt/mTOR signaling pathway in gastric cancer. (PMID:34455762)
• PLOD1 acts as a tumor promoter in glioma via activation of the HSF1 signaling pathway. (PMID:34845571)
• P3H4 and PLOD1 expression associates with poor prognosis in bladder cancer. (PMID:35149972)
• miR-449a ameliorates acute rejection after liver transplantation via targeting procollagen-lysine1,2-oxoglutarate5-dioxygenase 1 in macrophages. (PMID:36695693)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plod1a	ENSDARG00000059746
mus_musculus	Plod1	ENSMUSG00000019055
rattus_norvegicus	Plod1	ENSRNOG00000007763
drosophila_melanogaster	Plod	FBGN0036147
caenorhabditis_elegans		WBGENE00002497

Paralogs (5): PLOD3 (ENSG00000106397), COLGALT1 (ENSG00000130309), PLOD2 (ENSG00000152952), CERCAM (ENSG00000167123), COLGALT2 (ENSG00000198756)

Protein

Protein identifiers

Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 — Q02809 (reviewed: Q02809)

Alternative names: Lysyl hydroxylase 1

All UniProt accessions (3): Q02809, Q5JXB7, Q5JXB8

UniProt curated annotations — full annotation on UniProt →

Function. Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils. Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens. These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links.

Subunit / interactions. Homodimer. Identified in a complex with P3H3 and P3H4.

Subcellular location. Rough endoplasmic reticulum membrane.

Disease relevance. Ehlers-Danlos syndrome, kyphoscoliotic type, 1 (EDSKSCL1) [MIM:225400] A form of Ehlers-Danlos syndrome, a group of connective tissue disorders characterized by skin hyperextensibility, articular hypermobility, and tissue fragility. EDSKSCL1 is an autosomal recessive form characterized by severe muscle hypotonia at birth, generalized joint laxity, scoliosis at birth, and scleral fragility and rupture of the ocular globe. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q02809-1	1	yes
Q02809-2	2

RefSeq proteins (2): NP_000293, NP_001303249 (=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, PF25238, PF25342

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[collagen] + 2-oxoglutarate + O2 = (5R)-5-hydroxy-L-lysyl-[collagen] + succinate + CO2 (RHEA:16569)

UniProt features (29 total): sequence variant 12, mutagenesis site 5, glycosylation site 4, binding site 3, signal peptide 1, chain 1, splice variant 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02809-F1	93.04	0.89

Functional residue map

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

Catalytic / active sites (1): 718

Ligand- & substrate-binding residues (3): 656; 658; 708

Glycosylation sites (4): 686, 163, 197, 538

Mutagenesis-validated functional residues (5):

Position	Phenotype
369	loss of activity.
656	loss of enzyme activity.
658	loss of enzyme activity.
706	loss of enzyme activity.
708	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 429 (showing top): MODULE_93, MULLIGHAN_NPM1_SIGNATURE_3_UP, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MODULE_478, GNF2_PTX3, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_OXYGEN_LEVELS, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (6): response to hypoxia (GO:0001666), epidermis development (GO:0008544), collagen fibril organization (GO:0030199), collagen biosynthetic process (GO:0032964), obsolete hydroxylysine biosynthetic process (GO:0046947), peptidyl-lysine hydroxylation (GO:0017185)

GO Molecular Function (8): iron ion binding (GO:0005506), procollagen-lysine 5-dioxygenase activity (GO:0008475), L-ascorbic acid binding (GO:0031418), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (8): obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), rough endoplasmic reticulum membrane (GO:0030867), extracellular exosome (GO:0070062), catalytic complex (GO:1902494), 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
oxidoreductase activity	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
response to stress	1
response to decreased oxygen levels	1
tissue development	1
extracellular matrix organization	1
biosynthetic process	1
collagen metabolic process	1
protein hydroxylation	1
peptidyl-lysine modification	1
transition metal ion binding	1
2-oxoglutarate-dependent dioxygenase activity	1
catalytic activity, acting on a protein	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum membrane	1
rough endoplasmic reticulum	1
bounding membrane of organelle	1
extracellular vesicle	1
protein-containing complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1414 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLOD1	P4HA2	O15460	887
PLOD1	P4HA1	P13674	871
PLOD1	CHST14	Q8NCH0	823
PLOD1	ZNF469	Q96JG9	800
PLOD1	LOX	P28300	756
PLOD1	P3H4	Q92791	738
PLOD1	COL5A2	P05997	714
PLOD1	FKBP14	Q9NWM8	679
PLOD1	CRTAP	O75718	667
PLOD1	PPIB	P23284	635
PLOD1	P3H1	Q32P28	619
PLOD1	COL5A1	P20908	609
PLOD1	P3H3	Q8IVL6	562
PLOD1	SLC39A13	Q96H72	560
PLOD1	ADAMTS2	O95450	556

IntAct

128 interactions, top by confidence:

A	B	Type	Score
KIF1B	YWHAZ	psi-mi:“MI:0914”(association)	0.740
HNRNPH2	PLOD1	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
PABIR2	YWHAQ	psi-mi:“MI:0914”(association)	0.610
Zfp36	CNOT1	psi-mi:“MI:0914”(association)	0.560
HNRNPH2	PLOD2	psi-mi:“MI:0914”(association)	0.530
P3H3	HSPA8	psi-mi:“MI:0914”(association)	0.530
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
HNRNPA1	PTCD1	psi-mi:“MI:0914”(association)	0.530
PLOD3	COL4A1	psi-mi:“MI:0914”(association)	0.530
COLQ	PLOD3	psi-mi:“MI:0914”(association)	0.530
COL1A1	GOLIM4	psi-mi:“MI:0914”(association)	0.500
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
U2SURP	SMNDC1	psi-mi:“MI:0914”(association)	0.480
ODF2	PLK1	psi-mi:“MI:0914”(association)	0.480
PLOD1	PDIA3	psi-mi:“MI:0408”(disulfide bond)	0.440
Lats2	MPDZ	psi-mi:“MI:0914”(association)	0.420
WDFY4	PLOD1	psi-mi:“MI:0915”(physical association)	0.400
LRRC47	PLOD1	psi-mi:“MI:0915”(physical association)	0.400
KIF3B	PLOD1	psi-mi:“MI:0915”(physical association)	0.400
COL2A1	PLOD1	psi-mi:“MI:0915”(physical association)	0.400
Hnrnph1	PRMT5	psi-mi:“MI:0915”(physical association)	0.400
Fam107b	PLOD2	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
Cdc26		psi-mi:“MI:0914”(association)	0.350

BioGRID (387): PLOD1 (Affinity Capture-MS), PLOD1 (Affinity Capture-MS), HNRNPH2 (Co-fractionation), PLOD1 (Co-fractionation), PLOD1 (Co-fractionation), POR (Co-fractionation), PLOD1 (Affinity Capture-MS), PLOD1 (Proximity Label-MS), PLOD1 (Proximity Label-MS), PLOD1 (Proximity Label-MS), PLOD1 (Proximity Label-MS), PLOD1 (Affinity Capture-MS), PLOD1 (Affinity Capture-MS), PLOD1 (Affinity Capture-MS), PLOD1 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH3, A1YGR5, A3KGW5, A5PMF6, A7MB73, O00469, O14638, O43909, O77588, P06802, P15396, P24802, P26572, P27115, P27808, P50127, P79948, P79949, P97675, Q02809, Q09325, Q32NJ7, Q3L7M0, Q5IGR6, Q5R5M5, Q5R9N3, Q5T4B2, Q5U309, Q5U483, Q5XPT3, Q5ZLK4, Q63321, Q66PG1, Q66PG2, Q66PG4, Q6DYE8, Q6NVG7, Q6P7A1, Q6P9A2, Q6PA90

Diamond homologs: A0JPH3, A3KGW5, A5PK45, A5PMF6, A7MB73, Q02809, Q17FB8, Q29NU5, Q5R9N3, Q5T4B2, Q5U309, Q5U483, Q5UQ62, Q5UQC3, Q6NVG7, Q7Q021, Q811A3, Q8IPK4, Q8IYK4, Q8K297, Q8NBJ5, Q9VTH0, O00469, O60568, O77588, P24802, Q20679, Q5R6K5, Q5U367, Q63321, Q9R0B9, Q9R0E1, Q9R0E2, Q6N063, P57033, P71398, Q50947, Q51116, A3KGZ2, P0DO23

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
minoxidil	“down-regulates quantity by repression”	PLOD1	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 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	8	17.9×	4e-06
Collagen biosynthesis and modifying enzymes	12	17.6×	2e-09
Maturation of DENV proteins	7	12.8×	2e-04
Collagen degradation	7	10.6×	6e-04
mRNA Polyadenylation	10	7.6×	2e-04
Anchoring of the basal body to the plasma membrane	7	6.8×	6e-03
Processing of Capped Intron-Containing Pre-mRNA	8	5.7×	6e-03
Neddylation	12	4.9×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	13.7×	5e-03
autophagosome maturation	5	13.4×	5e-03
cellular response to amino acid stimulus	5	11.7×	9e-03
G1/S transition of mitotic cell cycle	7	10.7×	2e-03
collagen fibril organization	6	10.3×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1434 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	69
Likely pathogenic	50
Uncertain significance	512
Likely benign	610
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073871	NM_000302.4(PLOD1):c.145C>T (p.Gln49Ter)	Pathogenic
1404450	NM_000302.4(PLOD1):c.2025C>G (p.Tyr675Ter)	Pathogenic
1413244	NC_000001.10:g.(?12020683)(12027168_?)dup	Pathogenic
14364	NM_000302.4(PLOD1):c.955C>T (p.Arg319Ter)	Pathogenic
14365	NC_000001.11:g.(11959822_11959973)_(11968469_11968718)dup	Pathogenic
14368	NM_000302.4(PLOD1):c.1651-2del	Pathogenic
14369	NM_000302.3(PLOD1):c.1756_1902del	Pathogenic
14370	NM_000302.4(PLOD1):c.1533C>G (p.Tyr511Ter)	Pathogenic
14371	NM_000302.4(PLOD1):c.579+1G>A	Pathogenic
14372	NM_000302.4(PLOD1):c.1836G>C (p.Trp612Cys)	Pathogenic
1452011	NM_000302.4(PLOD1):c.1170_1192del (p.Asn391fs)	Pathogenic
1454300	NM_000302.4(PLOD1):c.1646del (p.Glu549fs)	Pathogenic
1455652	NM_000302.4(PLOD1):c.272del (p.Lys91fs)	Pathogenic
1460062	NC_000001.10:g.(?12014867)(12014970_?)del	Pathogenic
1702256	NM_000302.4(PLOD1):c.1362del (p.Tyr455fs)	Pathogenic
1980006	NM_000302.4(PLOD1):c.331del (p.Arg111fs)	Pathogenic
2089294	NM_000302.4(PLOD1):c.1711G>T (p.Glu571Ter)	Pathogenic
2108622	NM_000302.4(PLOD1):c.1365C>G (p.Tyr455Ter)	Pathogenic
2111795	NM_000302.4(PLOD1):c.1813C>T (p.Gln605Ter)	Pathogenic
2422835	NC_000001.10:g.(?12008013)(12008144_?)del	Pathogenic
2450248	NM_000302.4(PLOD1):c.1790del (p.Pro597fs)	Pathogenic
2702181	NM_000302.4(PLOD1):c.1698T>A (p.Cys566Ter)	Pathogenic
2733827	NM_000302.4(PLOD1):c.153dup (p.Asn52fs)	Pathogenic
2735026	NM_000302.4(PLOD1):c.180del (p.Glu62fs)	Pathogenic
2750647	NM_000302.4(PLOD1):c.274G>T (p.Glu92Ter)	Pathogenic
2761296	NM_000302.4(PLOD1):c.1281C>A (p.Tyr427Ter)	Pathogenic
2770105	NC_000001.11:g.11963531GA[1]	Pathogenic
2808247	NM_000302.4(PLOD1):c.1670_1671delinsAA (p.Trp557Ter)	Pathogenic
2829883	NM_000302.4(PLOD1):c.1256G>A (p.Trp419Ter)	Pathogenic
2839393	NM_000302.4(PLOD1):c.707_710del (p.Leu236fs)	Pathogenic

SpliceAI

3621 predictions. Top by Δscore:

Variant	Effect	Δscore
1:11934851:GGAGG:G	donor_gain	1.0000
1:11934852:GAGGG:G	donor_gain	1.0000
1:11934853:A:T	donor_gain	1.0000
1:11934854:GG:G	donor_gain	1.0000
1:11934855:GG:G	donor_gain	1.0000
1:11934861:G:GT	donor_gain	1.0000
1:11947971:TGCA:T	acceptor_loss	1.0000
1:11947972:GCA:G	acceptor_loss	1.0000
1:11947974:A:AG	acceptor_gain	1.0000
1:11947974:A:C	acceptor_loss	1.0000
1:11947975:G:GA	acceptor_gain	1.0000
1:11947975:GA:G	acceptor_gain	1.0000
1:11947975:GAC:G	acceptor_gain	1.0000
1:11947975:GACA:G	acceptor_gain	1.0000
1:11947975:GACAA:G	acceptor_gain	1.0000
1:11948066:AGGT:A	donor_loss	1.0000
1:11948068:GTAA:G	donor_loss	1.0000
1:11949772:GGC:G	acceptor_gain	1.0000
1:11949902:GACAG:G	donor_gain	1.0000
1:11949905:AGGTA:A	donor_loss	1.0000
1:11949906:GGTA:G	donor_loss	1.0000
1:11949907:G:T	donor_loss	1.0000
1:11950340:C:A	acceptor_gain	1.0000
1:11950343:T:TA	acceptor_gain	1.0000
1:11950348:T:A	acceptor_gain	1.0000
1:11950349:G:A	acceptor_gain	1.0000
1:11950353:ACAG:A	acceptor_loss	1.0000
1:11950354:CA:C	acceptor_loss	1.0000
1:11950355:A:AG	acceptor_gain	1.0000
1:11950355:A:AT	acceptor_loss	1.0000

AlphaMissense

4784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:11972890:T:C	F641L	1.000
1:11972892:T:A	F641L	1.000
1:11972892:T:G	F641L	1.000
1:11972942:A:T	D658V	1.000
1:11964651:T:A	W446R	0.999
1:11964651:T:C	W446R	0.999
1:11967071:T:A	W579R	0.999
1:11967071:T:C	W579R	0.999
1:11967073:G:C	W579C	0.999
1:11967073:G:T	W579C	0.999
1:11972900:G:C	R644P	0.999
1:11972935:C:G	H656D	0.999
1:11972941:G:C	D658H	0.999
1:11972942:A:C	D658A	0.999
1:11972942:A:G	D658G	0.999
1:11972943:T:A	D658E	0.999
1:11972943:T:G	D658E	0.999
1:11972948:C:T	S660F	0.999
1:11974668:T:C	F682L	0.999
1:11974669:T:C	F682S	0.999
1:11974669:T:G	F682C	0.999
1:11974670:C:A	F682L	0.999
1:11974670:C:G	F682L	0.999
1:11974746:C:G	H708D	0.999
1:11974777:G:C	R718P	0.999
1:11974794:T:C	F724L	0.999
1:11974796:C:A	F724L	0.999
1:11974796:C:G	F724L	0.999
1:11964223:C:A	N417K	0.998
1:11964223:C:G	N417K	0.998

dbSNP variants (sampled 300 via entrez): RS1000073734 (1:11937661 G>A), RS1000148160 (1:11958302 G>A), RS1000189982 (1:11932862 G>A), RS1000209206 (1:11959514 C>T), RS1000228206 (1:11968745 T>A,C), RS1000378724 (1:11936531 AT>A,ATT), RS1000528794 (1:11934398 G>T), RS1000534978 (1:11970483 C>A,T), RS1000637366 (1:11965086 C>T), RS1000651728 (1:11962791 A>T), RS1000752381 (1:11968180 C>CT), RS1000820922 (1:11960668 T>A,C,G), RS1000920714 (1:11959182 A>C), RS1000954641 (1:11968353 T>C), RS1001005936 (1:11949165 G>T)

Disease associations

OMIM: gene MIM:153454 | disease phenotypes: MIM:225400, MIM:607086, MIM:130000, MIM:148300

GenCC curated gene-disease

Disease	Classification	Inheritance
Ehlers-Danlos syndrome, kyphoscoliotic type 1	Definitive	Autosomal recessive

Mondo (8): Ehlers-Danlos syndrome, kyphoscoliotic type 1 (MONDO:0016002), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), Ehlers-Danlos syndrome (MONDO:0020066), myopathy (MONDO:0005336), hydrocephalus (MONDO:0001150), omphalocele (MONDO:0019015), keratoconus (MONDO:0015486), mitral valve prolapse (MONDO:0004910)

Orphanet (6): Kyphoscoliotic Ehlers-Danlos syndrome due to lysyl hydroxylase 1 deficiency (Orphanet:1900), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Ehlers-Danlos syndrome (Orphanet:98249), Omphalocele (Orphanet:660), OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000243	Trigonocephaly
HP:0000286	Epicanthus
HP:0000377	Abnormal pinna morphology
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000563	Keratoconus
HP:0000592	Blue sclerae
HP:0000618	Blindness
HP:0000678	Dental crowding
HP:0000767	Pectus excavatum
HP:0000883	Thin ribs
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000974	Hyperextensible skin
HP:0000977	Soft skin
HP:0000978	Bruising susceptibility
HP:0000987	Atypical scarring of skin
HP:0000993	Molluscoid pseudotumors

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004603_159	Platelet count	1.000000e-25
GCST004607_5	Plateletcrit	2.000000e-38
GCST004923_1	Tuberculosis	1.000000e-11
GCST005575_26	Moyamoya disease	1.000000e-10
GCST006166_46	Diastolic blood pressure x alcohol consumption interaction (2df test)	4.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0004329	alcohol drinking
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004535	Ehlers-Danlos Syndrome	C14.907.454.240; C15.378.463.515.240; C16.131.831.428; C16.320.850.260; C17.300.200.310; C17.800.804.428; C17.800.827.260
D006849	Hydrocephalus	C10.228.140.602
D007640	Keratoconus	C11.204.627
D008945	Mitral Valve Prolapse	C14.280.484.400.500
C536198	Ehlers-Danlos syndrome type 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465300 (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
5.80	IC50	1600	nM	CHEMBL5422717
5.77	IC50	1700	nM	CHEMBL5431602
5.64	IC50	2300	nM	CHEMBL5433830
5.37	IC50	4300	nM	CHEMBL1089782
5.32	IC50	4800	nM	CHEMBL5401981
5.19	IC50	6400	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-(4-methylpiperazin-1-yl)phenyl]-3-pyridin-4-ylpropane-1,3-dione	2016722: Inhibition of human recombinant LH1 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	1.6000	uM
1-(3-morpholin-4-ylphenyl)-3-pyridin-3-ylpropane-1,3-dione	2016722: Inhibition of human recombinant LH1 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	1.7000	uM
1-(3-morpholin-4-ylphenyl)-3-pyridin-4-ylpropane-1,3-dione	2016722: Inhibition of human recombinant LH1 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	2.3000	uM
4,4,4-trifluoro-1-pyridin-3-ylbutane-1,3-dione	2016722: Inhibition of human recombinant LH1 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	4.3000	uM
4,4,4-trifluoro-1-pyridin-4-ylbutane-1,3-dione	2016722: Inhibition of human recombinant LH1 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	2016722: Inhibition of human recombinant LH1 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	6.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	4
sodium arsenite	decreases expression, increases expression	2
Doxorubicin	affects cotreatment, affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
beta-lapachone	decreases expression	1
sodium bichromate	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
coumarin	affects phosphorylation	1
nivalenol	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation	1
demethoxycurcumin	decreases expression, decreases reaction	1
4-hydroxy-equilenin	decreases expression	1
K 7174	decreases expression	1
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Acetylcysteine	decreases reaction, decreases expression	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
CHEMBL5370455	Binding	Inhibition of human recombinant LH1 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

7 cell lines: 6 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AN08	GM13425	Finite cell line	Male
CVCL_AN09	GM13426	Finite cell line	Female
CVCL_AN10	GM13427	Finite cell line	Male
CVCL_C7MJ	GM28475	Finite cell line	Female
CVCL_C7MK	GM28476	Finite cell line	Female
CVCL_C7ML	GM28477	Finite cell line	Male
CVCL_XR63	HAP1 PLOD1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT01323764	PHASE4	COMPLETED	ShuntCheck Versus Radionuclide in Evaluating Shunt Function in Symptomatic NPH Patients
NCT01685450	PHASE4	UNKNOWN	NIMIP: Non Invasive Measurement of the Intracranial Pressure
NCT03513757	PHASE4	COMPLETED	Dexmedetomidine and Propofol for Pediatric MRI Sedation
NCT07547826	PHASE4	NOT_YET_RECRUITING	Efficacy and Cost-Effectiveness of Topical Vancomycin Powder in Preventing Pediatric Ventriculoperitoneal Shunt Infections Across Different Etiologies
NCT01485211	PHASE4	COMPLETED	Corneal Thickness Changes During Corneal Collagen Cross-linking With Ultraviolet-A Irradiation and Riboflavin
NCT02119039	PHASE4	COMPLETED	Effect of CACICOL20 on Corneal Epithelial Healing After Cross-linking in Patients With Keratoconus
NCT03245853	PHASE4	COMPLETED	Epi-On Corneal Crosslinking for Keratoconus
NCT03429569	PHASE4	UNKNOWN	Cross-Linking ACcéléré Iontophorèse Confocal kératocONE
NCT04427956	PHASE4	COMPLETED	Corneal Crosslinking Treatment Study
NCT07474870	PHASE4	NOT_YET_RECRUITING	Outcomes of CTAK Surgery
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT01225614	PHASE3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT00196196	PHASE3	COMPLETED	A Precision and Accuracy Study of the Codman Valve Position Verification (VPV) System.
NCT00286104	PHASE3	COMPLETED	Impact of Ventricular Catheter Used With Antimicrobial Agents on Patients With a Ventricular Catheter
NCT01936272	PHASE3	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Shunt vs ETV/CPC for PIH in Ugandan Infants
NCT02425761	PHASE3	UNKNOWN	The CSF Shunt Entry Site Trial
NCT02512809	PHASE3	TERMINATED	Isoflurane-induced Neuroinflammation in Children With Hydrocephalus
NCT04177914	PHASE3	RECRUITING	HCRN Endoscopic Versus Shunt Treatment of Hydrocephalus in Infants
NCT00371202	PHASE3	UNKNOWN	Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty With the Big Bubble Technique for Keratoconus
NCT00647699	PHASE3	COMPLETED	Corneal Collagen Cross-linking for Progressive Keratoconus
NCT00815256	PHASE3	UNKNOWN	Safety and Effectiveness of Collagen Cross Linking in Progressive Mild and Moderate Keratoconus
NCT00887900	PHASE3	COMPLETED	Deep Anterior Lamellar Keratoplasty (DALK)
NCT01112072	PHASE3	UNKNOWN	Corneal Collagen Crosslinking and Intacs for Keratoconus and Ectasia
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT00652470	PHASE2	COMPLETED	A Study Comparing Two Treatments for Infants With Hydrocephalus
NCT00278564	PHASE1	TERMINATED	Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases
NCT05001750	PHASE1	RECRUITING	Prophylactic Antibiotics Useful With Antibiotic Impregnated External Ventricular Drains (EVDs)?
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT06783803	Not specified	ACTIVE_NOT_RECRUITING	Application of Linkage Analysis in the Identification of Novel Hereditary Factors in Familial Aneurysms
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices