PLOD2

Summary

PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2, HGNC:9082) is a protein-coding gene on chromosome 3q24, encoding Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (O00469). Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens.

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. Mutations in the coding region of this gene are associated with Bruck syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 5352 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bruck syndrome 2 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 537 total — 18 pathogenic, 15 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 38 tissues, sQTL in 13 (q < 0.05)
• Phenotypes (HPO): 26
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.21 (unconstrained)
• MANE Select transcript: NM_182943

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9082
Approved symbol	PLOD2
Name	procollagen-lysine,2-oxoglutarate 5-dioxygenase 2
Location	3q24
Locus type	gene with protein product
Status	Approved
Aliases	LH2, TLH
Ensembl gene	ENSG00000152952
Ensembl biotype	protein_coding
OMIM	601865
Entrez	5352

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 25 protein_coding, 18 nonsense_mediated_decay, 12 retained_intron, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000282903

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 2, TSL 4: 1, TSL 5: 1

ENST00000282903, ENST00000360060, ENST00000460520, ENST00000461497, ENST00000469350, ENST00000475505, ENST00000478436, ENST00000480704, ENST00000494950, ENST00000495700, ENST00000703517, ENST00000703518, ENST00000703519, ENST00000703520, ENST00000703521, ENST00000703522, ENST00000703523, ENST00000703524, ENST00000703525, ENST00000703526, ENST00000703527, ENST00000703528, ENST00000703529, ENST00000706626, ENST00000706627, ENST00000706631, ENST00000706632, ENST00000706633, ENST00000706634, ENST00000706635, ENST00000706636, ENST00000902447, ENST00000930098, ENST00000956312, ENST00000956313, ENST00000956314, ENST00000956315, ENST00000956316, ENST00000956317, ENST00000956318, ENST00000956319, ENST00001000681, ENST00001000682, ENST00001000684, ENST00001000685, ENST00001000686, ENST00001015828, ENST00001015829, ENST00001015830, ENST00001015831, ENST00001015832, ENST00001015833, ENST00001015834, ENST00001113069, ENST00001113070, ENST00001118816, ENST00001118817, ENST00001128052

RefSeq mRNA: 2 — MANE Select: NM_182943 NM_000935, NM_182943

CCDS: CCDS3131, CCDS3132

Canonical transcript exons

ENST00000282903 — 20 exons

Exon	Start	End
ENSE00001008019	146110285	146110448
ENSE00001008021	146104279	146104342
ENSE00001131687	146106532	146106644
ENSE00001339129	146077862	146077924
ENSE00001891544	146102755	146102852
ENSE00003509154	146121112	146121248
ENSE00003546073	146124138	146124229
ENSE00003989124	146076782	146076895
ENSE00003989126	146088586	146088711
ENSE00003989136	146086787	146086908
ENSE00003989140	146073287	146073352
ENSE00003989143	146081738	146081863
ENSE00003989152	146091800	146091901
ENSE00003989161	146071042	146071167
ENSE00003989168	146085169	146085273
ENSE00003989170	146071277	146071423
ENSE00003989173	146069440	146070872
ENSE00003989179	146072561	146072665
ENSE00003989190	146160881	146161184
ENSE00003989195	146079116	146079257

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 110.6321 / max 2677.0866, expressed in 1547 samples.

Highest expression (Bgee): tibia, calcaneal tendon, jejunal mucosa, cartilage tissue, periodontal ligament.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PLOD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 13 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 51 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Esophagus Mucosa	eqtl	1.7e-44	+0.41	3:146151677:G:A
Skin Sun Exposed Lower leg	eqtl	3.1e-42	+0.34	3:146149944:G:C
Muscle Skeletal	eqtl	3.8e-39	+0.62	3:146140606:A:G
Skin Not Sun Exposed Suprapubic	eqtl	2.8e-32	-0.33	3:146145808:C:CTGG
Testis	eqtl	5.8e-28	-0.39	3:146155281:G:A
Esophagus Muscularis	eqtl	1.1e-23	-0.25	3:146091963:T:C
Nerve Tibial	eqtl	1.3e-21	-0.28	3:146096697:T:C
Artery Tibial	eqtl	2.7e-15	-0.18	3:146081000:A:G
Minor Salivary Gland	eqtl	4.1e-15	-0.52	3:146129261:A:C
Esophagus Gastroesophageal Junction	eqtl	8.5e-15	-0.27	3:146072275:CAT:C
Prostate	eqtl	1.1e-14	+0.33	3:146155281:G:A
Brain Spinal cord cervical c-1	eqtl	1.6e-11	+0.71	3:146080812:T:A
Cells Cultured fibroblasts	eqtl	1.9e-11	+0.12	3:146118401:G:T
Lung	eqtl	5.2e-11	-0.19	3:146117596:A:G
Brain Hippocampus	eqtl	2.2e-10	-0.28	3:146058886:G:T
Heart Atrial Appendage	sqtl	4.0e-10	-0.44	3:146117955:T:C
Nerve Tibial	sqtl	9.6e-10	-0.39	3:146128541:T:A
Lung	sqtl	2.1e-09	-0.34	3:146094374:G:A
Cells Cultured fibroblasts	sqtl	3.4e-09	+0.20	3:146126353:G:GA
Stomach	eqtl	6.8e-09	-0.24	3:146145808:C:CTGG

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
44900	101.1661	1530
44898	4.5927	1336
44902	3.3106	1162
44899	0.3486	169
44897	0.3290	168
44892	0.2223	93
44896	0.1943	87
44904	0.1830	58
202957	0.1493	65
44905	0.1166	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.17	gold quality
calcaneal tendon	UBERON:0003701	98.78	gold quality
jejunal mucosa	UBERON:0000399	98.52	gold quality
cartilage tissue	UBERON:0002418	98.42	gold quality
periodontal ligament	UBERON:0008266	97.96	gold quality
islet of Langerhans	UBERON:0000006	97.77	gold quality
pericardium	UBERON:0002407	97.72	gold quality
choroid plexus epithelium	UBERON:0003911	97.69	gold quality
type B pancreatic cell	CL:0000169	96.97	gold quality
smooth muscle tissue	UBERON:0001135	96.45	gold quality
saphenous vein	UBERON:0007318	96.06	gold quality
duodenum	UBERON:0002114	95.79	gold quality
gall bladder	UBERON:0002110	95.21	gold quality
colonic epithelium	UBERON:0000397	95.15	gold quality
mucosa of stomach	UBERON:0001199	95.02	gold quality
thyroid gland	UBERON:0002046	94.90	gold quality
left lobe of thyroid gland	UBERON:0001120	94.80	gold quality
stromal cell of endometrium	CL:0002255	94.79	gold quality
parietal pleura	UBERON:0002400	94.77	gold quality
ventricular zone	UBERON:0003053	94.71	gold quality
ascending aorta	UBERON:0001496	94.44	gold quality
germinal epithelium of ovary	UBERON:0001304	94.30	gold quality
thoracic aorta	UBERON:0001515	94.30	gold quality
adipose tissue	UBERON:0001013	94.23	gold quality
tendon	UBERON:0000043	94.17	gold quality
synovial joint	UBERON:0002217	94.08	gold quality
connective tissue	UBERON:0002384	93.99	gold quality
layer of synovial tissue	UBERON:0007616	93.91	gold quality
right lobe of thyroid gland	UBERON:0001119	93.78	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.73	gold quality
aorta	UBERON:0000947	93.63	gold quality
colonic mucosa	UBERON:0000317	93.57	gold quality
pleura	UBERON:0000977	93.52	gold quality
descending thoracic aorta	UBERON:0002345	93.52	gold quality
omental fat pad	UBERON:0010414	93.46	gold quality
peritoneum	UBERON:0002358	93.44	gold quality
rectum	UBERON:0001052	93.41	gold quality
tibial artery	UBERON:0007610	93.12	gold quality
endothelial cell	CL:0000115	93.11	gold quality
popliteal artery	UBERON:0002250	93.11	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.74	gold quality
renal glomerulus	UBERON:0000074	92.63	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.52	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.48	gold quality
metanephric glomerulus	UBERON:0004736	92.43	gold quality
placenta	UBERON:0001987	92.41	gold quality
renal medulla	UBERON:0000362	92.22	gold quality
liver	UBERON:0002107	92.17	gold quality
left coronary artery	UBERON:0001626	92.11	gold quality
myometrium	UBERON:0001296	92.07	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.88	gold quality
coronary artery	UBERON:0001621	91.86	gold quality
lower esophagus	UBERON:0013473	91.86	gold quality
pancreas	UBERON:0001264	91.81	gold quality
metanephros	UBERON:0000081	91.76	gold quality
tendon of biceps brachii	UBERON:0008188	91.72	gold quality
large intestine	UBERON:0000059	91.71	gold quality
visceral pleura	UBERON:0002401	91.70	gold quality
colon	UBERON:0001155	91.66	gold quality
sigmoid colon	UBERON:0001159	91.46	gold quality
esophagus squamous epithelium	UBERON:0006920	91.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.19	gold quality
vermiform appendix	UBERON:0001154	91.14	gold quality
transverse colon	UBERON:0001157	90.96	gold quality
blood vessel layer	UBERON:0004797	90.94	gold quality
pigmented layer of retina	UBERON:0001782	90.86	gold quality
retina	UBERON:0000966	90.83	gold quality
intestine	UBERON:0000160	90.76	gold quality
right coronary artery	UBERON:0001625	90.74	gold quality
ovary	UBERON:0000992	90.73	gold quality
body of uterus	UBERON:0009853	90.62	gold quality
right lobe of liver	UBERON:0001114	90.48	gold quality
right adrenal gland cortex	UBERON:0035827	90.29	gold quality
cortex of kidney	UBERON:0001225	90.06	gold quality
right ovary	UBERON:0002118	89.95	gold quality
decidua	UBERON:0002450	89.92	gold quality
ileal mucosa	UBERON:0000331	89.85	gold quality
left ovary	UBERON:0002119	89.73	gold quality
body of pancreas	UBERON:0001150	89.52	gold quality
metanephros cortex	UBERON:0010533	89.50	gold quality
left adrenal gland	UBERON:0001234	89.45	gold quality
right atrium auricular region	UBERON:0006631	89.34	gold quality
left adrenal gland cortex	UBERON:0035825	89.12	gold quality
adrenal cortex	UBERON:0001235	89.06	gold quality
adrenal gland	UBERON:0002369	89.06	gold quality
cranial nerve II	UBERON:0000941	88.99	gold quality
caecum	UBERON:0001153	88.98	gold quality
right adrenal gland	UBERON:0001233	88.87	gold quality
uterus	UBERON:0000995	88.83	gold quality
urethra	UBERON:0000057	88.81	gold quality
endometrium	UBERON:0001295	88.79	gold quality
kidney epithelium	UBERON:0004819	88.78	gold quality
mucosa of transverse colon	UBERON:0004991	88.72	gold quality
cardiac atrium	UBERON:0002081	88.66	gold quality
female reproductive system	UBERON:0000474	88.59	gold quality
thoracic mammary gland	UBERON:0005200	88.52	gold quality
mammary gland	UBERON:0001911	88.46	gold quality
esophagus	UBERON:0001043	88.44	gold quality
adrenal tissue	UBERON:0018303	88.37	gold quality
seminal vesicle	UBERON:0000998	88.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-21	yes	889.11
E-MTAB-6678	yes	397.54
E-MTAB-6701	yes	59.74
E-HCAD-10	yes	36.47
E-MTAB-8410	yes	33.37
E-CURD-112	yes	18.42
E-ANND-3	yes	11.89

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Thyroid gland	tissue	75.7	medium
Placenta	tissue	63.5	medium
Adipose tissue	tissue	46.1	low
Liver	tissue	41.7	medium
Corpus callosum	tissue	40.7
Duodenum	tissue	36.6	medium
Smooth muscle	tissue	33.7	low
Retina	tissue	33.3
Spinal cord	tissue	32.6
Appendix	tissue	31.0	low
Small intestine	tissue	28.5	medium
Medulla oblongata	tissue	28.0
Gallbladder	tissue	28.0	medium
Colon	tissue	26.5	medium
Ovary	tissue	24.9	not detected
Periaqueductal gray	tissue	24.5
Midbrain	tissue	24.4
Rectum	tissue	23.3	medium
Substantia nigra	tissue	23.3
Kidney	tissue	20.6	medium
Thalamus	tissue	19.8
Hippocampal formation	tissue	19.4
Putamen	tissue	19.0
Superior colliculi	tissue	18.7
Pons	tissue	18.4
Septum	tissue	18.0
Hypothalamus	tissue	17.9
Ventral forebrain	tissue	17.4
Urinary bladder	tissue	17.1	low
Stomach 1	tissue	15.6	medium
Amygdala	tissue	15.5
Endometrium 1	tissue	15.3	low
Adrenal gland	tissue	15.2	medium
Choroid plexus	tissue	14.9
Basal ganglia	tissue	14.0	medium
Esophagus	tissue	13.8	medium
Cerebral cortex	tissue	13.7	medium
Retrosplenial cortex	tissue	13.7
Parathyroid gland	tissue	12.8	low
Olfactory bulb	tissue	12.7
Pancreas	tissue	12.6	medium
Seminal vesicle	tissue	12.5	low
Motor cortex	tissue	12.5
Occipital cortex	tissue	12.0
Retrosplenial and cingulate cortex	tissue	11.8
Somatosensory cortex	tissue	11.8
Prefrontal cortex	tissue	11.7
Entorhinal cortex	tissue	11.7
Insular cortex	tissue	11.7
Temporal cortex	tissue	11.2
Cerebellum	tissue	10.5	low
Vagina	tissue	9.6	low
Fallopian tube	tissue	9.2	medium
Lung	tissue	8.9	medium
Prostate	tissue	8.1	low
Breast	tissue	7.8	low
Thymus	tissue	7.7
Cervix	tissue	7.3	medium
Pituitary gland	tissue	7.3
Salivary gland	tissue	6.7	low

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — White matter (40.7), Blood vessel (37.9), Ventral spinal cord (32.6), Dorsal spinal cord (29.1), Dorsal hippocampus (19.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYB, PITX2

miRNA regulators (miRDB)

Targeting PLOD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 101 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-182-5P	99.87	74.03	2589

Functional genomics

gnomAD constraint: pLI 6.81e-07, LOEUF 1.21, missense Z 0.248 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000282903 — one region, missense o/e 0.99. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Characterization of Plod2 and Plod3 gene structure in mouse and comparison to PLOD1, PLOD2, and PLOD3 gene structure in human. (PMID:11334715)
• 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)
• PLOD2 has a important role in fibrotic processes (PMID:12881513)
• a boy who had congenital contractures with pterygia at birth and severe OI-like osteopenia and multiple fractures and he was shown to be homozygous for a novel mutation leading to an Arg598His substitution in PLOD2 (PMID:15523624)
• 3 patients with mixed phenotypes of Ehlers-Danlos Syndrome with decreased mRNAs for LH2 in skin fibroblasts; mutations not shown that could explain decreased expression; deficiency of LH2 may be caused by changes in other factors required for expression (PMID:15589118)
• alternate transcripts of LH2 may have specificity for hydroxylation of lysines in either telopeptide or helical collagen domains, so their relative expression determines the type of cross-links formed, thereby affecting collagen strength (PMID:15694128)
• Elevated formation of pyridinoline cross-links by profibrotic cytokines is associated with enhanced PLOD2 levels. (PMID:15955452)
• Data show that lysyl hydroxylase 2(long) exerts a bimodal function on collagen alpha(I) synthesis in human dermal fibroblasts. (PMID:16934803)
• TIA1 and TIAL1 regulate the alternate splicing of lysyl hydroxylase 2 (PMID:19110540)
• Missense mutations that cause Bruck syndrome affect enzymatic activity, folding, and oligomerization of LH2. (PMID:19762917)
• Fox-2 plays an integral role in the regulation of LH2 splicing, and decrease in LH2 mRNA in primary scleroderma cells may suggest a novel approach to strategies directed against scleroderma. (PMID:20131247)
• PLOD2 is a potential novel prognostic factor for HCC patients following surgery. (PMID:22098155)
• PLOD2 in addition to causing BS is also associated with AR-OI phenotypes of variable severity (PMID:22689593)
• Infrapatellar fat pad contributeS to the development of synovial fibrosis in the knee joint by increasing collagen production, PLOD2 expression, cell proliferation, and cell migration. (PMID:23666869)
• data indicate that HIF-1alpha controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors (PMID:23906982)
• TGFbeta induced PLOD2/LH2 expression in human synovial osteoarthritic fibroblasts through ALK5 signaling. (PMID:24192939)
• LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma. (PMID:25664850)
• findings reveal that TGFbeta1 induces a SP1- and SMAD3-dependent recruitment of histone modifying enzymes to the PLOD2 promoter other than the currently known TGFbeta1 downstream co-activators and epigenetic modifications (PMID:26432637)
• Results show that miR-26a and miR-26b were significantly downregulated in renal cell carcinoma clinical specimens and appeared to function as tumor suppressors through regulation of collagen cross-linking enzymes, LOXL2 and PLOD2, both of which function as oncogenes in this disease. (PMID:26983694)
• FKBP65 is linked to pyridinoline cross-linking by specifically mediating the dimerization of LH2. (PMID:27298363)
• PLOD2, which is associated with the stiffness of the extracellular matrix, was directly regulated by miR-26a-5p and miR-26b-5p and may be a good prognostic marker in patients with BC (PMID:27310702)
• Elevated fasting and postprandial C-terminal telopeptide after Roux-en-Y gastric bypass confers an increased risk of bone loss on recipients. (PMID:27555664)
• The finding that LH2 modifies collagen in the extracellular space challenges the current view that LH2 functions solely on the endoplasmic reticulum and could also have important implications for cancer biology. (PMID:27803159)
• This study reports for the first time the expression of PLOD2 in Brain Arteriovenous Malformations and suggests a potential role of PLOD2 in brain Arteriovenous Malformations pathophysiology. (PMID:28279775)
• knockdown of endogenous PLOD2 suppresses glioma cell proliferation, migration and invasion through modulating multiple EMT-associated factors via inactivation of PI3K/AKT signaling. (PMID:28410212)
• Only the mechanisms of PLOD2 regulated by HIF-1alpha, TGF-beta and microRNA-26a/b have been elaborated. (PMID:28415047)
• Hypoxia upregulated PLOD2 protein in U87 and U251 human glioma cell lines. (PMID:28423580)
• Gain- and loss-of-function studies and orthotopic implantation metastasis model pinpointed that PLOD2 promotes NSCLC metastasis directly by enhancing migration and indirectly by inducing collagen reorganization. (PMID:29072684)
• Mutations in PLOD2 cause Bruck Syndrome (PMID:29177700)
• Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2. (PMID:29178448)
• Findings suggest that Acanthamoeba polyphaga mimivirus L230 co-evolved with human collagen lysyl hydroxylases (LHs). (PMID:29410444)
• High PLOD2 expression is associated with peritoneal dissemination in gastric cancer. (PMID:29603227)
• High PLOD2 expression is associated with Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. (PMID:30105440)
• High PLOD2 expression is associated with Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer. (PMID:30167909)
• adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways (PMID:30563531)
• Hypoxia and TGF-beta1 increase PLOD2 expression through HIF and SMAD pathway. (PMID:31391253)
• Procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 are potential prognostic indicators in patients with clear cell renal cell carcinoma. (PMID:31446433)
• We found that PLOD2 could serve as a prognostic marker in patients with LSCC and confer drug resistance in LSCC by increasing CSC-like traits; in addition, a Wnt-responsive CSC pathway was identified. (PMID:31455288)
• PLOD2 promotes aerobic glycolysis and cell progression in colorectal cancer by upregulating HK2. (PMID:31742425)
• Hypoxia-induced PLOD2 regulates invasion and epithelial-mesenchymal transition in endometrial carcinoma cells. (PMID:31872384)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plod2	ENSDARG00000011821
mus_musculus	Plod2	ENSMUSG00000032374
rattus_norvegicus	Plod2	ENSRNOG00000030183
drosophila_melanogaster	Plod	FBGN0036147
caenorhabditis_elegans		WBGENE00002497

Paralogs (5): PLOD1 (ENSG00000083444), PLOD3 (ENSG00000106397), COLGALT1 (ENSG00000130309), CERCAM (ENSG00000167123), COLGALT2 (ENSG00000198756)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1347007) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 23 distinct phenotype terms.

Mouse phenotype (MP)	Records
thin ventricular wall	1
abnormal coat/ hair morphology	1
abnormal locomotor behavior	1
limb grasping	1
impaired righting response	1
abnormal embryo size	1
decreased embryo size	1
abnormal coat/hair pigmentation	1
prenatal lethality	1
abnormal spine curvature	1
decreased fetal size	1
abnormal heart ventricle morphology	1
abnormal patella morphology	1
abnormal tendon morphology	1
increased apoptosis	1
decreased fetal weight	1
neonatal lethality, complete penetrance	1
embryonic lethality during organogenesis, complete penetrance	1
preweaning lethality, complete penetrance	1
lethality throughout fetal growth and development, incomplete penetrance	1
increased endoplasmic reticulum stress	1
joint contracture	1
abnormal patellar ligament morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5R6K5	99.5%	Diamond
Bos taurus	O77588	94.2%	Diamond
Xenopus laevis	Q5U483	91.7%	Diamond
Gallus gallus	P24802	79.1%	Diamond
Acanthamoeba polyphaga mimivirus	Q5UQC3	39.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LNCSRLR	ncRNA	109729161
PLSCR4	protein-coding	57088
PLSCR2	protein-coding	57047

Protein

Protein identifiers

Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 — O00469 (reviewed: O00469)

Alternative names: Lysyl hydroxylase 2

All UniProt accessions (9): O00469, A0A994J3M7, A0A994J6E6, A0A994J6S5, A0A9L9PX47, A0A9L9PXC2, C9JXZ0, E7ETU9, F8WEW3

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subcellular location. Rough endoplasmic reticulum membrane. Cytoplasm.

Tissue specificity. Highly expressed in pancreas and muscle. Isoform 1 and isoform 2 are expressed in the majority of the examined cell types. Isoform 2 is specifically expressed in skin, lung, dura and aorta.

Disease relevance. Bruck syndrome 2 (BRKS2) [MIM:609220] An autosomal recessive disease characterized by generalized osteopenia, congenital joint contractures, fragile bones with onset of fractures in infancy or early childhood, short stature, severe limb deformity, progressive scoliosis, and pterygia. It is distinguished from osteogenesis imperfecta by the absence of hearing loss and dentinogenesis imperfecta, and by the presence of clubfoot and congenital joint limitations. The disease is caused by variants affecting the gene represented in this entry. The molecular defect leading to Bruck syndrome is an aberrant cross-linking of bone collagen, due to underhydroxylation of lysine residues within the telopeptides of type I collagen, whereas the lysine residues in the triple helix are normal.

Isoforms (3)

UniProt ID	Names	Canonical?
O00469-1	1, A	yes
O00469-2	2, B
O00469-3	3

RefSeq proteins (2): NP_000926, NP_891988* (*=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, PF13704, 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)

Substrate kinetics (BRENDA)

17 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
(ILE-LYS-GLY)3	0.31–0.8	6
ASCORBATE	0.05–0.35	5
(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
ALA-ARG-GLY-MET-LYS-GLY-HIS-ARG-GLY-(PRO-PRO-GLY	0.2	1
PEPTIDE (IKG)3	0.169	1
PROCOLLAGEN L-LYSINE	0.1	1

Catalyzed reactions (Rhea)

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

UniProt features (39 total): sequence variant 18, glycosylation site 7, splice variant 3, binding site 3, modified residue 3, signal peptide 1, chain 1, domain 1, active site 1, sequence conflict 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00469-F1	92.63	0.88

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Metabolic proteins, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of the musculoskeletal system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoli

Antibody reliability (HPA): IH approved · IF uncertain

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)

Position	Role
728

Ligand- & substrate-binding residues (3)

Position	Role
666	Fe cation
668	Fe cation
718	Fe cation

Post-translational modifications (3)

Type	Positions
Phosphothreonine	320
Phosphotyrosine	323
N6-succinyllysine	704

Glycosylation sites (7)

Type	Positions
N-linked (glcnac…) asparagine	63, 209, 297, 365, 522, 696, 725

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-1650814	Collagen biosynthesis and modifying enzymes	curated
R-HSA-1474290	Collagen formation	—
R-HSA-1474244	Extracellular matrix organization	—

MSigDB gene sets: 407 (showing top): MODULE_52, chr3q24, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, CROONQUIST_NRAS_SIGNALING_DN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, MENSE_HYPOXIA_UP, MODULE_478, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, GNF2_PTX3, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, DOANE_BREAST_CANCER_CLASSES_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS

GO Biological Process (3): response to hypoxia (GO:0001666), collagen fibril organization (GO:0030199), collagen biosynthetic process (GO:0032964)

GO Molecular Function (7): iron ion binding (GO:0005506), procollagen-lysine 5-dioxygenase activity (GO:0008475), L-ascorbic acid binding (GO:0031418), 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): cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), rough endoplasmic reticulum membrane (GO:0030867), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062), rough endoplasmic reticulum (GO:0005791)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Collagen formation	1
Extracellular matrix organization	1

GO top-level categories

29 GO namespaces:

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
extracellular matrix organization	1
biosynthetic process	1
collagen metabolic process	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
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cellular anatomical structure	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
external encapsulating structure	1
extracellular vesicle	1
endoplasmic reticulum	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
collagen biosynthetic process	BP	direct assay
response to hypoxia	BP	expression pattern
cytoplasm	CC	mutant phenotype
extracellular exosome	CC	high-throughput assay
procollagen-lysine 5-dioxygenase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,344 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLOD2	FKBP10	Q96AY3	842
PLOD2	CRTAP	O75718	733
PLOD2	TMEM38B	Q9NVV0	732
PLOD2	P3H1	Q32P28	723
PLOD2	P4HA1	P13674	723
PLOD2	SDSL	Q96GA7	718
PLOD2	SDS	P20132	678
PLOD2	P4HA2	O15460	678
PLOD2	ZNF469	Q96JG9	670
PLOD2	CHST14	Q8NCH0	660
PLOD2	LOX	P28300	657
PLOD2	SERPINH1	P29043	644
PLOD2	IFITM5	A6NNB3	623
PLOD2	SERPINF1	P36955	607
PLOD2	SEC24D	O94855	594

IntAct

Human interaction partners of PLOD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

28 partners by confidence:

Partner	Interaction type	MIscore	Records
HNRNPH2	association	0.530	2
PLOD3	association	0.530	2
PPIB	physical association	0.400	1
ADIPOQ	association	0.350	2
C1QTNF1	association	0.350	2
ATF2	association	0.350	1
ATG5	association	0.350	1
C1QTNF3	association	0.350	1
COL10A1	association	0.350	1
COL21A1	association	0.350	1
COL23A1	association	0.350	1
COL6A2	association	0.350	1
COL8A2	association	0.350	1
COLEC10	association	0.350	1
COLEC11	association	0.350	1
COLGALT2	association	0.350	1
COLQ	association	0.350	1
E6	association	0.350	1
EPHA7	association	0.350	1
FCN1	association	0.350	1
FOXA1	association	0.350	1
ITGB1BP2	association	0.350	1
MAN1A1	association	0.350	1
PLOD1	association	0.350	1
SLC47A1	association	0.350	1
EPHA10	proximity	0.270	1
TCTN1	proximity	0.270	1
RUVBL2	physical association	0.000	1

BioGRID (223 interactions; top human partners by supporting records): FBXO6 (Affinity Capture-MS; 3 records), COLQ (Affinity Capture-MS; 2 records), FKBP4 (Co-fractionation; 2 records), GANAB (Co-fractionation; 2 records), HNRNPH2 (Affinity Capture-MS; 2 records), ITGB1BP2 (Affinity Capture-Luminescence; 2 records), NCL (Co-fractionation; 2 records), PLOD1 (Affinity Capture-MS; 2 records), RUVBL2 (Affinity Capture-MS; 2 records), XPO7 (Affinity Capture-MS; 2 records), ACTB (Co-fractionation), ADIPOQ (Affinity Capture-MS), AHNAK2 (Co-fractionation), AMBRA1 (Proximity Label-MS), AP2B1 (Co-fractionation)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
PLOD2-FKBP10 complex	2	FKBP10, PLOD2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 28 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 biosynthesis and modifying enzymes	9	66.7×	4e-13
Collagen chain trimerization	5	56.4×	1e-06

Disease & clinical

Genetic variants

Variant evidence for PLOD2: 537 ClinVar records (33 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	18
Likely pathogenic	15
Uncertain significance	226
Likely benign	160
Benign	60

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 33 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
41424	NM_182943.3(PLOD2):c.1559dup (p.Val523fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
632404	NM_182943.3(PLOD2):c.1417C>T (p.Arg473Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
391827	NM_182943.3(PLOD2):c.1127+2T>C	Pathogenic	criteria provided, single submitter	1
988376	NM_182943.3(PLOD2):c.1764G>T (p.Trp588Cys)	Pathogenic	criteria provided, single submitter	1
1075750	NM_182943.3(PLOD2):c.1275G>A (p.Trp425Ter)	Pathogenic	criteria provided, single submitter	1
1323472	NM_182943.3(PLOD2):c.67del (p.Cys23fs)	Pathogenic	criteria provided, single submitter	1
1425319	NM_182943.3(PLOD2):c.1287G>A (p.Trp429Ter)	Pathogenic	criteria provided, single submitter	1
1696826	NM_182943.3(PLOD2):c.648C>A (p.Cys216Ter)	Pathogenic	criteria provided, single submitter	1
2711440	NM_182943.3(PLOD2):c.1712del (p.Tyr570_Ser571insTer)	Pathogenic	criteria provided, single submitter	1
2747849	NM_182943.3(PLOD2):c.818G>A (p.Trp273Ter)	Pathogenic	criteria provided, single submitter	1
2781350	NM_182943.3(PLOD2):c.1345del (p.Gln449fs)	Pathogenic	criteria provided, single submitter	1
2826246	NM_182943.3(PLOD2):c.893dup (p.Ser299fs)	Pathogenic	criteria provided, single submitter	1
3727774	NM_182943.3(PLOD2):c.58del (p.Trp20fs)	Pathogenic	criteria provided, single submitter	1
4292588	NM_182943.3(PLOD2):c.1501-2A>G	Pathogenic	criteria provided, single submitter	1
4812155	NM_182943.3(PLOD2):c.1207_1208insA (p.Leu403fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PLOD2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 39 predictions of 2,059):

Position(s)	Effect	Δscore	Sites
3:146071040–146071041	donor_loss	1.0000	4
3:146071168–146071169	acceptor_loss	1.0000	5
3:146071275–146071276	donor_loss	1.0000	5
3:146071424–146071425	acceptor_loss	1.0000	5
3:146077118	donor_gain	1.0000
3:146079114–146079115	donor_loss	1.0000	5
3:146079258	acceptor_loss	1.0000	3
3:146081732	donor_gain	1.0000
3:146081736–146081737	donor_loss	1.0000	4
3:146081864–146081865	acceptor_loss	1.0000	6

AlphaMissense

2,139 missense substitutions predicted likely pathogenic (of 5,043 scored), across 497 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M491	9	0.935	0.992
D668	8	0.999	1.000
H718	8	0.999	1.000
D610	8	0.998	0.999
H716	8	0.998	0.999
H666	8	0.997	1.000
F734	8	0.996	1.000
D596	8	0.995	0.998
F651	8	0.994	1.000
H710	8	0.994	0.999
D564	8	0.990	0.998
H667	8	0.988	0.996
D736	8	0.988	0.996
D213	8	0.986	0.996
F692	8	0.984	1.000
D443	8	0.982	0.998
H612	8	0.979	0.996
N536	8	0.977	0.998
D488	8	0.976	0.990
D490	8	0.970	0.995

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

9 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.09e-09
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	1.57e-08
Lung Adenocarcinoma (validation)	unfavorable	1.01e-06
Kidney Chromophobe (TCGA)	unfavorable	1.01e-05
Liver Hepatocellular Carcinoma (validation)	unfavorable	2.42e-05
Kidney Renal Clear Cell Carcinoma (validation)	unfavorable	0.000244
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000256
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000266
Lung Adenocarcinoma (TCGA)	unfavorable	0.000293

Disease associations

OMIM: gene MIM:601865 | disease phenotypes: MIM:609220, MIM:166200, MIM:119570, MIM:119800

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Bruck syndrome 2	Definitive	Autosomal recessive	3
Bruck syndrome	Supportive	Autosomal recessive

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Arthrogryposis	green
DDG2P	green
Fetal anomalies	green
Osteogenesis imperfecta	green
Paediatric disorders	green
Skeletal dysplasia	green

Mondo (6): Bruck syndrome 2 (MONDO:0012217), osteogenesis imperfecta (MONDO:0019019), cleft soft palate (MONDO:0007338), clubfoot (MONDO:0007342), femoral agenesis/hypoplasia (MONDO:0016032), Bruck syndrome (MONDO:0017195)

Orphanet (5): Bruck syndrome (Orphanet:2771), Osteogenesis imperfecta (Orphanet:666), Isolated femoral agenesis/hypoplasia (Orphanet:1987), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Cleft velum (Orphanet:99772)

HPO phenotypes

26 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000325	Triangular face
HP:0000768	Pectus carinatum
HP:0000926	Platyspondyly
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0001059	Pterygium
HP:0001371	Flexion contracture
HP:0001387	Joint stiffness
HP:0001762	Talipes equinovarus
HP:0002093	Respiratory insufficiency
HP:0002645	Wormian bones
HP:0002650	Scoliosis
HP:0002659	Increased susceptibility to fractures
HP:0002757	Recurrent fractures
HP:0002804	Arthrogryposis multiplex congenita
HP:0002808	Kyphosis
HP:0002980	Femoral bowing
HP:0002987	Elbow flexion contracture
HP:0003080	Hydroxyprolinuria
HP:0004322	Short stature
HP:0006380	Knee flexion contracture
HP:0006487	Bowing of the long bones
HP:6000807	Cervical C6/C7 vertebrae fusion
HP:6001098	Metaphyseal undermodelling

GWAS associations

4 associations:

Study	Trait	p-value
GCST008839_526	Height	1e-12
GCST001762_271	Obesity-related traits	2e-7
GCST002934_10	Zinc levels	4e-6
GCST004750_43	Squamous cell lung carcinoma	5e-6

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C537407	Bruck syndrome 2 *(supp.)*
C562950	Cleft Soft Palate *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4742261 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465273 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

8 measured of 11 human assays (15 total across all organisms); most potent 8 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5433830	IC50	2700 nM
CHEMBL5422717	IC50	4700 nM
CHEMBL5401981	IC50	4800 nM
CHEMBL5431602	IC50	4800 nM
CHEMBL1875205	IC50	5000 nM
CHEMBL1089782	IC50	5200 nM
CHEMBL1443628	IC50	5200 nM
CHEMBL5421171	IC50	7600 nM

ChEMBL bioactivities

8 potent at pChembl≥5 of 8 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	IC50	300	nM	CHEMBL5433830
6.30	IC50	500	nM	CHEMBL5422717
6.00	IC50	1000	nM	CHEMBL1443628
5.82	IC50	1500	nM	CHEMBL5431602
5.72	IC50	1900	nM	CHEMBL5401981
5.47	IC50	3400	nM	CHEMBL1089782
5.30	IC50	5000	nM	CHEMBL1875205
5.12	IC50	7600	nM	CHEMBL5421171

PubChem BioAssay actives

8 with measured affinity, of 19 total; 8 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	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	0.3000	uM
1-[3-(4-methylpiperazin-1-yl)phenyl]-3-pyridin-4-ylpropane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	0.5000	uM
1-phenyl-3-pyridin-4-ylpropane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	1.0000	uM
1-(3-morpholin-4-ylphenyl)-3-pyridin-3-ylpropane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	1.5000	uM
4,4,4-trifluoro-1-pyridin-4-ylbutane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	1.9000	uM
4,4,4-trifluoro-1-pyridin-3-ylbutane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	3.4000	uM
1-phenyl-3-pyridin-3-ylpropane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	5.0000	uM
4,4,4-trifluoro-1-(4-fluorophenyl)butane-1,3-dione	2016721: Inhibition of human recombinant LH2 expressed in CHO cells incubated for 30 mins by luciferase-based Succinate-GloTM JmjC Demethylase/Hydroxylase Assay	ic50	7.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Particulate Matter	increases abundance, increases expression, affects cotreatment, affects expression, decreases expression	6
bisphenol A	affects expression, affects cotreatment, decreases methylation, decreases expression, increases expression	5
Estradiol	affects expression, affects binding, increases expression, affects cotreatment	4
Cyclosporine	affects expression, decreases expression	4
methylmercuric chloride	decreases expression, increases expression, affects cotreatment	3
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Ethanol	increases expression, decreases expression, increases abundance, affects cotreatment	3
Oxygen	increases expression	3
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	3
sodium arsenite	affects cotreatment, decreases expression	2
cobaltous chloride	increases expression	2
cadmium sulfate	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
chloropicrin	affects expression, decreases expression	2
entinostat	affects cotreatment, increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, decreases methylation	2
Copper	affects binding, increases expression	2
Fluorouracil	decreases expression, increases expression, affects response to substance	2
Isoniazid	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	decreases methylation, increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
tungsten carbide	affects binding, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713774	Binding	Protac activity at CRBN/PLOD2 in human BxPC-3 cells assessed as PLOD2 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3E3	Abcam HEK293T PLOD2 KO	Transformed cell line	Female
CVCL_TE69	HAP1 PLOD2 (-) 1	Cancer cell line	Male
CVCL_XR64	HAP1 PLOD2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 124 trials:

NCT	Phase	Status	Title
NCT00131469	Phase 4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	Phase 4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	Phase 4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	Phase 4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	Phase 4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	Phase 4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT04564430	Phase 4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	Phase 4	COMPLETED	Clubfoot Tenotomy Trial
NCT00001305	Phase 3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	Phase 3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	Phase 3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	Phase 3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	Phase 3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	Phase 3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	Phase 3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	Phase 3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	Phase 3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	Phase 3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT00063479	Phase 2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	Phase 2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	Phase 2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	Phase 2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	Phase 2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	Phase 2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	Phase 2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	Phase 2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	Phase 2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	Phase 2	RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT00705120	Phase 1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	Phase 1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	Phase 1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	Phase 1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	Phase 1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)
NCT06086613	Phase 1	COMPLETED	A First-in-Human Study Evaluating AGA2115 in Adult Healthy Volunteers
NCT05125809	Phase 2/3	ACTIVE_NOT_RECRUITING	Setrusumab vs Placebo for Osteogenesis Imperfecta
NCT03706482	Phase 1/2	ACTIVE_NOT_RECRUITING	Boost Brittle Bones Before Birth
NCT04623606	Phase 1/2	UNKNOWN	Boost to Brittle Bones - Stem Cell Transplantation for Treatment of Brittle Bones
NCT05559801	Phase 1/2	NOT_YET_RECRUITING	Mesenchymal Cell Therapy in Osteogenesis Imperfecta (OI)
NCT00001594	Not specified	COMPLETED	Evaluation and Intervention for the Effects of Osteogenesis Imperfecta
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00187018	Not specified	COMPLETED	Marrow Mesenchymal Cell Therapy for Osteogenesis Imperfecta: A Pilot Study
NCT00655681	Not specified	COMPLETED	Prevention of Post Operative Bone Loss in Children
NCT02432625	Not specified	RECRUITING	BBD Longitudinal Study of Osteogenesis Imperfecta
NCT02531087	Not specified	ACTIVE_NOT_RECRUITING	Urinary Biomarkers of OI Pathobiology
NCT02542540	Not specified	TERMINATED	Effects of a Physical Rehabilitation Program Using the Nintendo Wii on Children With Osteogenesis Imperfecta (OI)
NCT02793063	Not specified	COMPLETED	Osteogenesis Imperfecta (OI) Quality of Life Survey Pilot Project 2
NCT02814591	Not specified	UNKNOWN	Development of a Non-invasive Assessment of Human Bone Quality Using Spatially Offset Raman Spectroscopy
NCT02868294	Not specified	UNKNOWN	Preventive Fixation of Lower Limbs in Osteogenesis Imperfecta (Brittle Bone Disease) With the Highlight of the Fassier-Duval
NCT02934451	Not specified	ACTIVE_NOT_RECRUITING	Dental Malocclusion and Craniofacial Development in OI
NCT03029312	Not specified	COMPLETED	Whole Body Vibration Training in Children With Osteogenesis Imperfecta and Limited Mobility
NCT03072303	Not specified	COMPLETED	Pregnancy in Osteogenesis Imperfecta (OI) Registry
NCT03557567	Not specified	COMPLETED	NGS Strategy Effectiveness in Molecular Diagnosis
NCT03575221	Not specified	COMPLETED	Natural History of the Collagen-Related Disorder Osteogenesis Imperfecta and Genotype Phenotype Correlation
NCT03841188	Not specified	COMPLETED	Nutritional Interventional in Pediatric Patients With Osteogenesis Imperfecta
NCT04009733	Not specified	COMPLETED	Epigenetic Regulation of Osteogenesis Imperfecta Severity : miROI Study
NCT04115774	Not specified	RECRUITING	Registry of Osteogenesis Imperfecta
NCT04119388	Not specified	COMPLETED	Evaluation of the Benefits of Adaptive Physical Activity in Children and Adolescents With Osteogenesis Imperfecta
NCT04169568	Not specified	COMPLETED	Osteogenesis Imperfecta Blood Pressure Study
NCT04231916	Not specified	COMPLETED	High Resolution Thermal Imaging to Identify Vertebral Fractures in Children and Young People With Osteogenesis Imperfecta
NCT04282408	Not specified	COMPLETED	Experimental Evaluation of Back Braces for the Treatment of Spinal Deformity Produced With 3D Printing Technology

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PLOD2 across ~30M SureChEMBL compounds — explore on Sugi Predict.