ASPN

Summary

ASPN (asporin, HGNC:14872) is a protein-coding gene on chromosome 9q22.31, encoding Asporin (Q9BXN1). Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system.

This gene encodes a cartilage extracellular protein that is member of the small leucine-rich proteoglycan family. The encoded protein may regulate chondrogenesis by inhibiting transforming growth factor-beta 1-induced gene expression in cartilage. This protein also binds collagen and calcium and may induce collagen mineralization. Polymorphisms in the aspartic acid repeat region of this gene are associated with a susceptibility to osteoarthritis, and also with intervertebral disc disease. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 54829 — RefSeq curated summary.

At a glance

• Gene–disease (curated): osteoarthritis susceptibility 3 (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 42 total — 2 pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈4% of expected missense variation)
• GTEx eGene: eQTL in 7 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 6
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.53 (unconstrained)
• MANE Select transcript: NM_017680

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14872
Approved symbol	ASPN
Name	asporin
Location	9q22.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20129, SLRR1C, PLAP-1
Ensembl gene	ENSG00000106819
Ensembl biotype	protein_coding
OMIM	608135
Entrez	54829

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 nonsense_mediated_decay

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

ENST00000375543, ENST00000375544, ENST00000650794, ENST00000651738, ENST00000907468, ENST00000907469, ENST00000907470, ENST00001116555, ENST00001136630

RefSeq mRNA: 2 — MANE Select: NM_017680 NM_001193335, NM_017680

Canonical transcript exons

ENST00000375544 — 8 exons

Exon	Start	End
ENSE00000711478	92459632	92459770
ENSE00000711479	92460474	92460567
ENSE00000711481	92464919	92465029
ENSE00000869933	92470669	92470781
ENSE00000869936	92466358	92466571
ENSE00001031659	92482293	92482506
ENSE00001467400	92474624	92474927
ENSE00003647036	92456205	92457485

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 99.71.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9316 / max 412.0078, expressed in 427 samples.

Highest expression (Bgee): tendon of biceps brachii, synovial joint, periodontal ligament, calcaneal tendon, tendon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASPN is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

8 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Heart Atrial Appendage	eqtl	5.9e-03	+0.15	9:92596168:C:G
Esophagus Mucosa	eqtl	6.4e-03	+0.16	9:92189537:A:G
Muscle Skeletal	eqtl	1.2e-02	-0.10	9:92665540:CTGAG:C
Thyroid	eqtl	1.3e-02	-0.10	9:92517306:A:G
Artery Aorta	eqtl	1.5e-02	+0.24	9:92309812:G:C
Esophagus Mucosa	sqtl	2.9e-02	-0.94	9:91912000:A:ACTC
Pancreas	eqtl	3.6e-02	+0.37	9:92669067:TCTA:T
Lung	eqtl	5.0e-02	+0.17	9:91682051:T:C

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
101432	3.4884	362
101431	3.1477	303
101429	0.1382	71
101430	0.0902	50
101428	0.0672	33

Top tissues by expression

showing 100 of 276 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.71	gold quality
synovial joint	UBERON:0002217	99.70	gold quality
periodontal ligament	UBERON:0008266	99.64	gold quality
calcaneal tendon	UBERON:0003701	99.63	gold quality
tendon	UBERON:0000043	99.14	gold quality
saphenous vein	UBERON:0007318	99.06	gold quality
blood vessel layer	UBERON:0004797	98.97	gold quality
visceral pleura	UBERON:0002401	98.73	gold quality
right coronary artery	UBERON:0001625	98.71	gold quality
ascending aorta	UBERON:0001496	97.34	gold quality
thoracic aorta	UBERON:0001515	97.33	gold quality
vena cava	UBERON:0004087	97.03	gold quality
skin of hip	UBERON:0001554	97.02	gold quality
descending thoracic aorta	UBERON:0002345	96.95	gold quality
gall bladder	UBERON:0002110	96.92	gold quality
coronary artery	UBERON:0001621	96.16	gold quality
cartilage tissue	UBERON:0002418	96.14	gold quality
left coronary artery	UBERON:0001626	95.79	gold quality
nipple	UBERON:0002030	95.67	gold quality
layer of synovial tissue	UBERON:0007616	95.60	gold quality
aorta	UBERON:0000947	95.38	gold quality
pleura	UBERON:0000977	95.31	gold quality
pylorus	UBERON:0001166	95.29	gold quality
decidua	UBERON:0002450	94.95	gold quality
myometrium	UBERON:0001296	94.86	gold quality
parietal pleura	UBERON:0002400	93.94	gold quality
popliteal artery	UBERON:0002250	93.88	gold quality
tibial artery	UBERON:0007610	93.86	gold quality
superficial temporal artery	UBERON:0001614	93.76	gold quality
urethra	UBERON:0000057	92.71	gold quality
myocardium	UBERON:0002349	92.46	gold quality
heart right ventricle	UBERON:0002080	91.95	gold quality
smooth muscle tissue	UBERON:0001135	91.16	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.08	gold quality
cauda epididymis	UBERON:0004360	90.78	gold quality
body of uterus	UBERON:0009853	90.31	gold quality
cardia of stomach	UBERON:0001162	89.93	gold quality
colonic epithelium	UBERON:0000397	89.85	gold quality
trabecular bone tissue	UBERON:0002483	89.44	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.06	gold quality
endocervix	UBERON:0000458	88.68	gold quality
body of tongue	UBERON:0011876	88.35	gold quality
left uterine tube	UBERON:0001303	87.95	gold quality
apex of heart	UBERON:0002098	87.70	gold quality
connective tissue	UBERON:0002384	87.13	gold quality
adipose tissue	UBERON:0001013	86.76	gold quality
tibia	UBERON:0000979	86.71	gold quality
mammalian vulva	UBERON:0000997	86.54	gold quality
superior surface of tongue	UBERON:0007371	86.38	gold quality
left ventricle myocardium	UBERON:0006566	86.36	gold quality
heart	UBERON:0000948	86.33	gold quality
trachea	UBERON:0003126	86.24	gold quality
liver	UBERON:0002107	85.74	gold quality
tongue	UBERON:0001723	85.60	gold quality
pericardium	UBERON:0002407	85.59	gold quality
thoracic mammary gland	UBERON:0005200	85.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.56	gold quality
gluteal muscle	UBERON:0002000	85.43	gold quality
mammary gland	UBERON:0001911	85.40	gold quality
peritoneum	UBERON:0002358	85.32	gold quality
omental fat pad	UBERON:0010414	85.29	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.13	gold quality
cardiac atrium	UBERON:0002081	85.05	gold quality
triceps brachii	UBERON:0001509	84.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.71	gold quality
mammary duct	UBERON:0001765	84.58	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.36	gold quality
biceps brachii	UBERON:0001507	84.24	gold quality
rectum	UBERON:0001052	84.14	gold quality
right atrium auricular region	UBERON:0006631	83.93	gold quality
cardiac ventricle	UBERON:0002082	83.81	gold quality
heart left ventricle	UBERON:0002084	83.50	gold quality
epithelium of mammary gland	UBERON:0003244	83.20	gold quality
right lobe of liver	UBERON:0001114	83.17	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	82.95	gold quality
jejunum	UBERON:0002115	82.79	gold quality
uterus	UBERON:0000995	82.78	gold quality
renal medulla	UBERON:0000362	82.53	gold quality
fundus of stomach	UBERON:0001160	82.34	gold quality
right lung	UBERON:0002167	82.12	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.83	gold quality
lower esophagus	UBERON:0013473	81.78	gold quality
penis	UBERON:0000989	81.46	gold quality
dorsal root ganglion	UBERON:0000044	81.39	gold quality
ectocervix	UBERON:0012249	81.10	gold quality
pharyngeal mucosa	UBERON:0000355	80.95	gold quality
lung	UBERON:0002048	80.65	gold quality
muscle tissue	UBERON:0002385	80.35	gold quality
uterine cervix	UBERON:0000002	80.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.17	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	79.73	gold quality
thyroid gland	UBERON:0002046	79.45	gold quality
intestine	UBERON:0000160	79.40	gold quality
large intestine	UBERON:0000059	79.31	gold quality
jejunal mucosa	UBERON:0000399	79.28	gold quality
tibial nerve	UBERON:0001323	79.24	gold quality
duodenum	UBERON:0002114	79.24	gold quality
fallopian tube	UBERON:0003889	79.20	gold quality
colon	UBERON:0001155	78.94	gold quality
caecum	UBERON:0001153	78.71	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	2937.61
E-CURD-126	yes	1732.07
E-HCAD-10	yes	32.64
E-MTAB-10287	yes	26.47
E-MTAB-8410	yes	17.55
E-MTAB-10042	yes	9.00
E-MTAB-10553	yes	6.33
E-GEOD-124858	no	78.88
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 77 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Smooth muscle	tissue	103.1	not detected
Heart muscle	tissue	89.2	not detected
Endometrium 1	tissue	65.1	not detected
Gallbladder	tissue	61.7	not detected
Cervix	tissue	38.4	not detected
Liver	tissue	38.4	not detected
Adipose tissue	tissue	27.7	low
Spinal cord	tissue	19.6
Tongue	tissue	18.5
Small intestine	tissue	16.6	not detected
Lung	tissue	13.5	not detected
Pancreas	tissue	12.6	not detected
Urinary bladder	tissue	12.5	not detected
Skin 1	tissue	11.4	not detected
Breast	tissue	11.1	low
Seminal vesicle	tissue	11.0	not detected
Rectum	tissue	10.6	not detected
Colon	tissue	10.5	not detected
Kidney	tissue	10.5	not detected
Substantia nigra	tissue	10.3
Superior colliculi	tissue	9.8
Esophagus	tissue	9.5	not detected
Medulla oblongata	tissue	9.5
Epididymis	tissue	9.1	not detected
Olfactory bulb	tissue	9.1
Duodenum	tissue	9.0	not detected
Ovary	tissue	8.8	not detected
Cerebellum	tissue	8.3	not detected
Thyroid gland	tissue	8.3	not detected
Basal ganglia	tissue	8.0	not detected
Cerebral cortex	tissue	7.9	not detected
Corpus callosum	tissue	7.9
Periaqueductal gray	tissue	7.9
Insular cortex	tissue	7.9
Amygdala	tissue	7.8
Midbrain	tissue	7.6
Retrosplenial and cingulate cortex	tissue	7.6
Temporal cortex	tissue	7.6
Putamen	tissue	7.4
Ventral forebrain	tissue	7.4
Retrosplenial cortex	tissue	7.4
Skeletal muscle	tissue	7.3	not detected
Adrenal gland	tissue	7.1	not detected
Septum	tissue	7.0
Hippocampal formation	tissue	6.9
Entorhinal cortex	tissue	6.9
Thalamus	tissue	6.7
Prefrontal cortex	tissue	6.6
Somatosensory cortex	tissue	6.6
Motor cortex	tissue	6.5
Fallopian tube	tissue	6.5	not detected
Occipital cortex	tissue	6.5
Pons	tissue	6.3
Stomach 1	tissue	6.2	not detected
Hypothalamus	tissue	5.9
Appendix	tissue	5.4	not detected
Tonsil	tissue	5.2	not detected
Vagina	tissue	5.1	not detected
Placenta	tissue	4.0	not detected
Prostate	tissue	3.9	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Blood vessel (129.3), Dorsal spinal cord (19.6), Ventral spinal cord (13.5), White matter (7.9), Ventral hippocampus (6.9).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMAD3, SP1

miRNA regulators (miRDB)

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

showing 30 of 64 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-200A-5P	99.76	69.10	949

Functional genomics

gnomAD constraint: pLI 4.68e-09, LOEUF 1.53, missense Z 1.27 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000375544 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈4% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
9:92,457,291–92,474,739	336 / 379.3	0.89	no
9:92,474,740–92,474,786	4 / 19.0	0.21	yes (p 5.7e-04)
9:92,474,787–92,474,897	41 / 42.8	0.96	no

Literature-anchored findings (GeneRIF, showing 40)

• these findings provide another functional link between extracellular matrix proteins, TGF-beta activity and disease, suggesting new therapeutic strategies for osteoarthritis. (PMID:15640800)
• No significant differences were observed in any of the multiple comparisons performed in osteoarthritis and controls (PMID:16542493)
• expression may be associated with the process of cytodifferentiation of periodontal ligament cells (PMID:16632759)
• Association of the D14 allele with knee osteoarthritis susceptibility in Han Chinese. (PMID:17024313)
• the association of the ASPN D14 allele and knee OA has global relevance [meta-analysis] (PMID:17517696)
• This study further highlighted the significance of asporin in osteoarthritis. (PMID:17603749)
• Characterization of the human ASPN promoter region revealed a region from -126 to -82 that is sufficient for full promoter activity; however, TGF-beta1 failed to increase activity through the ASPN promoter. (PMID:17804408)
• describe mechanisms for asporin function and regulation in human articular cartilage; asporin blocks chondrogenesis and inhibits TGF-beta1-induced expression of matrix genes and the resulting chondrocyte phenotypes. (PMID:17827158)
• The frequency of the aspartic acid repeat polymorphism was examined. These results suggest that asporin may play a role in OA susceptibility of the knee in the Korean female population. (PMID:18178444)
• ASPN is a lumbar-disc degeneration (LDD) gene in Asians, and common risk factors may be considered for osteoarthritis and LDD. (PMID:18304494)
• Asporin is up-regulated in disease states. It binds to various growth factors, including TGF-beta and BMP-2, and negatively regulates their activity. By inhibiting binding of TGF-beta1 to its type II receptor, asporin forms a functional feedback loop. (PMID:18336287)
• These data suggest that polymorphisms within ASPN are not a major influence in susceptibility to hand or knee OA in US Caucasians. (PMID:18434216)
• In the discs of Caucasian subjects there was greatest expression of asporin in the more degenerate human discs in vivo. (PMID:19327154)
• Asporin has a role in osteoblast-driven collagen biomineralization activity. (PMID:19589127)
• The ratio of Asporin to TGF-beta1 (transforming growth factor-beta1) mRNA in patients with severe cartilage damage was higher than that in osteoartritis patients with mild cartilage damage (PMID:19997821)
• Association of an asporin repeat polymorphism with ankylosing spondylitis in Han Chinese population: a case-control study, is reported. (PMID:20144272)
• Our results show an obvious association between the D repeat polymorphism of ASPN and Developmental dysplasia of the hip (PMID:21329514)
• ASPN plays positive roles in the mineralization of dental pulp stem cells and predentin to dentin. (PMID:21413025)
• Data indicate that the expression of ASPN gene is finely regulated in cartilage and suggest a major role of Sp1. (PMID:21528154)
• mir-101 and mir-21 target PLAP-1 to regulate its expression during osteogenic differentiation of PDLCs. (PMID:22367347)
• Asporin is associated with hand osteoarthritis progression. (PMID:23357225)
• polymorphisms within the ASPN gene could influence knee osteoarthritis susceptibility (PMID:23733110)
• A meta-analysis suggest that the D-repeat of asporin gene (ASPN) may not be a major susceptibility locus in the Caucasian and Asian populations with knee osteoarthritis. (PMID:23942062)
• The asporin-encoding gene is a promising candidate as a susceptibility gene for osteoarthritis and degenerative disc disease. [Review] (PMID:24003854)
• Our data suggest that the D15 asporin allele could be considered a knee osteoarthritis risk allele significant only for women in the Iranian population. (PMID:24078942)
• This meta-analysis shows that the ASPN D14, D13, and D15 alleles are not associated with the development of osteoarthritis in Europeans and Asians. [Meta-Analysis] (PMID:24306268)
• Asporin may represent a new therapeutic target molecule for the development of drugs aimed at manipulating the cancer microenvironment. (PMID:24441039)
• D14-PLAP-1 suppressed BMP-2 signal transduction more efficiently than D13-PLAP-1; stronger affinity of D14-PLAP-1 protein to BMP-2 compared with D13-PLAP-1 protein. D repeat polymorphism of PLAP-1/asporin has influence on functions of PDL cells. (PMID:24453179)
• Our results showed that ASPN rs13301537 T to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population. (PMID:25030405)
• Osteomodulin, osteoglycin, and asporin appear to be distinctly regulated in osteoarthritis labrum compared to OA cartilage. (PMID:25371314)
• Collectively, our findings indicate that ASPN is upregulated and plays an oncogenic role in gastric cancer progression and metastasis by influencing the EGFR signaling pathway. (PMID:25673058)
• this is the first case-control study in Mexican women that suggests that menopause and the D-repeat polymorphism in the ASPN gene are associated with knee OA (PMID:26016288)
• To test the associations of ASPN variations with risk of subsequent oncologic outcomes. (PMID:26446945)
• Suggest that the D14 allele of the ASPN polymorphism could exert an influence on primary osteoarthritis of the knee etiology in a Mexican Mestizo population. (PMID:26620055)
• we found that asporin can be downregulated by bone morphogenetic protein 4 in Hs578T cells and its upregulation may be facilited by serum-free cultivation or by three dimensional growth (PMID:27409832)
• higher expression of asporin was noticed in CRC tissues and it was correlated with later clinical stage of the patients. Asporin promoted the migration and invasion of the tumor cells partially through an EGFR/Src/cortactin- signaling pathway. (PMID:27705916)
• High ASPN expression in stroma is associated with prostate cancer progression. (PMID:28152543)
• Asporin promotes epithelial mesenchymal transformation, invasion, and migration of pancreatic cancer cellss by activating CD44-AKT/ERK-NF-kappaB pathway in paracrine and autocrine manner. (PMID:28400334)
• our study provides evidence that asporin is an important risk factor in intervertebral disc degeneration. The identification of the intrinsic expression mechanisms of asporin provides further understanding of disc degeneration. (PMID:28646230)
• ASPN D-repeat polymorphism is not associated with an increased Knee Osteoarthritis risk. (PMID:28889984)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aspn	ENSDARG00000002192
mus_musculus	Aspn	ENSMUSG00000021388
rattus_norvegicus	Aspn	ENSRNOG00000015410

Paralogs (22): DCN (ENSG00000011465), RTN4R (ENSG00000040608), FLRT3 (ENSG00000125848), FLRT1 (ENSG00000126500), LRRC4 (ENSG00000128594), LRRC4B (ENSG00000131409), PODNL1 (ENSG00000132000), LRTM1 (ENSG00000144771), LRRC4C (ENSG00000148948), LRRTM1 (ENSG00000162951), LRRC15 (ENSG00000172061), PODN (ENSG00000174348), LRRTM4 (ENSG00000176204), BGN (ENSG00000182492), LRRC19 (ENSG00000184434), FLRT2 (ENSG00000185070), GP1BA (ENSG00000185245), RTN4RL1 (ENSG00000185924), RTN4RL2 (ENSG00000186907), NYX (ENSG00000188937), LRRC66 (ENSG00000188993), LRRTM3 (ENSG00000198739)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1913945) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal lens morphology	1
abnormal retina morphology	1
increased circulating HDL cholesterol level	1
abnormal skin morphology	1
decreased mean corpuscular volume	1
abnormal vitreous body morphology	1
abnormal auditory brainstem response	1
increased circulating cholesterol level	1
abnormal skin tensile strength	1
abnormal cutaneous collagen fibril morphology	1
abnormal glycosaminoglycan level	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
Pan troglodytes	Q5R1V9	100.0%	Diamond
Macaca fascicularis	Q9BGP6	100.0%	Diamond
Ovis aries	O46390	99.5%	Diamond
Bos taurus	P21809	99.5%	Diamond
Oryctolagus cuniculus	O46377	99.3%	Diamond
Equus caballus	O46403	99.3%	Diamond
Sus scrofa	Q9GKQ6	99.3%	Diamond
Canis lupus familiaris	O02678	97.8%	Diamond
Gallus gallus	P28675	97.5%	Diamond
Coturnix japonica	Q9DE68	97.5%	Diamond
Xenopus laevis	Q9IB75	85.9%	Diamond
Caenorhabditis elegans	G5EFX6	54.9%	Diamond
Branchiostoma floridae	C3YZ59	44.3%	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
MIR4670	ncRNA	100616351
ECM2	protein-coding	1842
CENPP	protein-coding	401541
IPPK	protein-coding	64768
OMD	protein-coding	4958
OGN	protein-coding	4969
NOL8	protein-coding	55035
SNORA84	snoRNA	100124534
MIR3651	ncRNA	100500918
IARS1	protein-coding	3376

Protein

Protein identifiers

Asporin — Q9BXN1 (reviewed: Q9BXN1)

Alternative names: Periodontal ligament-associated protein 1

All UniProt accessions (4): A0A494C084, A0A494C1J0, Q9BXN1, Q5TBF2

UniProt curated annotations — full annotation on UniProt →

Function. Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system. Inhibits BMP2-induced cytodifferentiation of PDL cells by preventing its binding to BMPR1B/BMP type-1B receptor, resulting in inhibition of BMP-dependent activation of SMAD proteins. Critical regulator of TGF-beta in articular cartilage and plays an essential role in cartilage homeostasis and osteoarthritis (OA) pathogenesis. Negatively regulates chondrogenesis in the articular cartilage by blocking the TGF-beta/receptor interaction on the cell surface and inhibiting the canonical TGF-beta/Smad signal. Binds calcium and plays a role in osteoblast-driven collagen biomineralization activity.

Subunit / interactions. Interacts with TGFB1, TGFB2 and TGFB3. DCN, BGN, and FMOD inhibit binding to TGFB1. Interacts with BMP2. Interacts in vitro with type II collagen. Interacts with type I collagen. DCN can inhibit collagen binding.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Higher levels in osteoarthritic articular cartilage, aorta, uterus. Moderate expression in small intestine, heart, liver, bladder, ovary, stomach, and in the adrenal, thyroid, and mammary glands. Low expression in trachea, bone marrow, and lung. Colocalizes with TGFB1 in chondrocytes within osteoarthritic (OA) lesions of articular cartilage.

Post-translational modifications. There is no serine/glycine dipeptide sequence expected for the attachment of O-linked glycosaminoglycans and this is probably not a proteoglycan. The O-linked polysaccharide on 54-Ser is probably the mucin type linked to GalNAc. The N-linked glycan at Asn-282 is composed of variable structures of GlcNAc, mannose, fucose, HexNAc and hexose.

Disease relevance. Osteoarthritis 3 (OS3) [MIM:607850] A degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to osteoarthritis is conferred by a triplet repeat expansion polymorphism. ASPN allele having 14 aspartic acid repeats in the N-terminal region of the protein (D14), is overrepresented relative to the common allele having 13 aspartic acid repeats (D13). The frequency of the D14 allele increases with disease severity. The D14 allele is also overrepresented in individuals with hip osteoarthritis. Intervertebral disc disease (IDD) [MIM:603932] A common musculo-skeletal disorder caused by degeneration of intervertebral disks of the lumbar spine. It results in low-back pain and unilateral leg pain. Disease susceptibility is associated with variants affecting the gene represented in this entry. Susceptibility to intervertebral disk disease, particularly lumbar disk degeneration, is conferred by a triplet repeat expansion polymorphism. ASPN allele having 14 aspartic acid repeats in the N-terminal region of the protein (D14), is associated with the disorder in some populations.

Domain organisation. The LRR 5 repeat can inhibit BMP2-induced cytodifferentiation and may be involved in the interaction with BMP2. The repeats LRR 10, LRR 11 and LRR 12 are involved in binding type I collagen. The poly-Asp region is involved in binding calcium.

Induction. By TGFB1.

Polymorphism. The poly-Asp region of ASPN is polymorphic and ranges at least from 11 to 17 Asp.

Similarity. Belongs to the small leucine-rich proteoglycan (SLRP) family. SLRP class I subfamily.

RefSeq proteins (2): NP_001180264, NP_060150* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR016352	SLRP_I_decor/aspor/byglycan	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050333	SLRP	Family

Pfam: PF01462, PF13855

UniProt features (24 total): repeat 11, disulfide bond 3, region of interest 2, glycosylation site 2, signal peptide 1, propeptide 1, compositionally biased region 1, chain 1, sequence conflict 1, domain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXN1-F1	85.71	0.77

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

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.

Disulfide bonds (3)

Type	Positions
Disulfide bond	75–81, 79–88, 333–366

Glycosylation sites (2)

Type	Positions
O-linked (galnac…) serine	55
N-linked (glcnac…) asparagine	282

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 2; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

2 pathways:

ID	Pathway	Evidence
R-HSA-3000178	ECM proteoglycans	—
R-HSA-1474244	Extracellular matrix organization	—

MSigDB gene sets: 173 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, MODULE_418, SMID_BREAST_CANCER_RELAPSE_IN_LUNG_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_TOOTH_MINERALIZATION, TURASHVILI_BREAST_CARCINOMA_DUCTAL_VS_LOBULAR_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_BONE_MINERALIZATION, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, NF1_Q6_01, GOBP_RESPONSE_TO_TRANSFORMING_GROWTH_FACTOR_BETA, GOMF_EXTRACELLULAR_MATRIX_STRUCTURAL_CONSTITUENT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_UP

GO Biological Process (5): bone mineralization (GO:0030282), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of tooth mineralization (GO:0070171), response to fluoride (GO:1902617), biomineral tissue development (GO:0031214)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), extracellular matrix structural constituent conferring compression resistance (GO:0030021)

GO Cellular Component (3): extracellular matrix (GO:0031012), cell projection (GO:0042995), gel phase of interstitial matrix (GO:0140150)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

18 GO namespaces:

Category	Terms
external encapsulating structure	2
ossification	1
biomineral tissue development	1
animal gross anatomical part developmental process	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
tooth mineralization	1
negative regulation of biomineral tissue development	1
regulation of tooth mineralization	1
response to chemical	1
tissue development	1
animal organ development	1
metal ion binding	1
binding	1
extracellular matrix structural constituent	1
cellular anatomical structure	1
interstitial matrix	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
bone mineralization	BP	direct assay
negative regulation of transforming growth factor beta receptor signaling pathway	BP	direct assay
extracellular matrix	CC	direct assay
calcium ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,402 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPN	MATN3	O15232	902
ASPN	FRZB	Q92765	894
ASPN	CTDSP2	O14595	850
ASPN	CILP	O75339	834
ASPN	HDAC11	Q96DB2	796
ASPN	GBA1	P04062	759
ASPN	GDF5	P43026	759
ASPN	COL11A1	P12107	751
ASPN	HDAC8	Q9BY41	721
ASPN	CTRB2	Q6GPI1	718
ASPN	CTRB1	P17538	718
ASPN	HDAC3	O15379	700
ASPN	HDAC2	Q92769	699
ASPN	HDAC1	Q13547	696
ASPN	THBS2	P35442	673

IntAct

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

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ITIH2	association	0.350	1

BioGRID (7 interactions; top human partners by supporting records): PSMD2 (Affinity Capture-Western; 2 records), ITIH2 (Affinity Capture-MS), RPL37A (Cross-Linking-MS (XL-MS)), SELM (Affinity Capture-MS), TRPC6 (Positive Genetic)

Disease & clinical

Genetic variants

Variant evidence for ASPN: 42 ClinVar records (2 pathogenic / likely pathogenic); 3 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	22
Likely benign	4
Benign	7

Top pathogenic / likely-pathogenic (2)

Showing all 2 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
1073961	NC_000009.11:g.(?95007241)(95237179_?)del	Pathogenic	criteria provided, single submitter	1
2425154	NC_000009.11:g.(?94485944)(95527026_?)del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ASPN’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.

AlphaMissense

890 missense substitutions predicted likely pathogenic (of 2,534 scored), across 223 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
N181	8	0.995	0.999
N112	8	0.990	0.999
N136	8	0.986	0.998
N160	8	0.986	0.998
N275	8	0.979	0.996
N299	8	0.973	0.995
N251	8	0.971	0.996
D108	8	0.962	0.992
N205	8	0.957	0.997
N352	8	0.957	0.995
N322	8	0.954	0.995
F217	8	0.933	0.985
D90	8	0.931	0.985
F191	8	0.925	0.992
F364	8	0.919	0.976
F332	8	0.918	0.993
F146	8	0.912	0.989
D249	8	0.906	0.978
S348	8	0.884	0.992
D260	8	0.881	0.955

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Breast Invasive Carcinoma)

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	unfavorable	2.46e-05
Ovary Serous Cystadenocarcinoma (validation)	unfavorable	0.000124
Stomach Adenocarcinoma (TCGA)	unfavorable	0.000254
Kidney Chromophobe (TCGA)	unfavorable	0.000258
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000589

Disease associations

OMIM: gene MIM:608135 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
osteoarthritis susceptibility 3	Limited	Autosomal dominant

Mondo (1): osteoarthritis susceptibility 3 (MONDO:0011923)

HPO phenotypes

6 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001387	Joint stiffness
HP:0002758	Osteoarthritis
HP:0002829	Arthralgia
HP:0006226	Osteoarthritis of the first carpometacarpal joint
HP:0006233	Osteoarthritis of the distal interphalangeal joint

GWAS associations

3 associations:

Study	Trait	p-value
GCST010725_3	Malaria	6e-6
GCST010725_70	Malaria	6e-6
GCST010725_91	Malaria	9e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	increases expression	2
Estradiol	decreases expression, affects expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
testosterone enanthate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
triadimefon	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
incobotulinumtoxinA	increases expression	1
Calcitriol	decreases expression	1
Dexamethasone	affects cotreatment, increases expression, decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression, decreases expression	1
Valproic Acid	decreases expression	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

15 trials:

NCT	Phase	Status	Title
NCT03414970	Phase 3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT06113055	Phase 2	UNKNOWN	Hereditary Sensory Neuropathy Serine Trial
NCT00461344	Phase 2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	Phase 2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT02134496	Not specified	COMPLETED	PACU Discharge Without Motorfunction Assessment After Spinal Anaesthesia
NCT01733407	Phase 1/2	COMPLETED	L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1
NCT00637364	Phase 1/2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	Phase 1/2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	Early Phase 1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	Early Phase 1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT07628634	Early Phase 1	RECRUITING	Feasibility Study on the Effect of a Methionine-Reduced Diet on Serum Levels in Pts w/ Solid Tumors
NCT01208974	Not specified	COMPLETED	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery