NKX3-2

Summary

NKX3-2 (NK3 homeobox 2, HGNC:951) is a protein-coding gene on chromosome 4p15.33, encoding Homeobox protein Nkx-3.2 (P78367). Transcriptional repressor that acts as a negative regulator of chondrocyte maturation.

Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in cell differentiation; negative regulation of chondrocyte differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including intestinal epithelial cell development; middle ear morphogenesis; and skeletal system development. Predicted to be located in chromatin. Predicted to be active in nucleus.

Source: NCBI Gene 579 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spondylo-megaepiphyseal-metaphyseal dysplasia (Definitive, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 185 total — 8 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 35
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001189

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:951
Approved symbol	NKX3-2
Name	NK3 homeobox 2
Location	4p15.33
Locus type	gene with protein product
Status	Approved
Aliases	NKX3B, NKX3.2
Ensembl gene	ENSG00000109705
Ensembl biotype	protein_coding
OMIM	602183
Entrez	579

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000382438

RefSeq mRNA: 1 — MANE Select: NM_001189 NM_001189

CCDS: CCDS3410

Canonical transcript exons

ENST00000382438 — 2 exons

Exon	Start	End
ENSE00000816719	13540830	13542528
ENSE00001492050	13543949	13544508

Expression profiles

Bgee: expression breadth broad, 90 present calls, max score 93.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0843 / max 10.0175, expressed in 32 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51412	0.0461	20
51411	0.0381	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	93.98	gold quality
muscle layer of sigmoid colon	UBERON:0035805	84.04	gold quality
cartilage tissue	UBERON:0002418	83.00	gold quality
sigmoid colon	UBERON:0001159	75.94	gold quality
lower esophagus muscularis layer	UBERON:0035833	69.48	gold quality
lower esophagus	UBERON:0013473	69.41	gold quality
colon	UBERON:0001155	68.61	gold quality
tendon of biceps brachii	UBERON:0008188	68.26	silver quality
large intestine	UBERON:0000059	68.03	gold quality
transverse colon	UBERON:0001157	67.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.24	gold quality
intestine	UBERON:0000160	63.57	gold quality
spleen	UBERON:0002106	62.67	gold quality
omental fat pad	UBERON:0010414	62.67	gold quality
peritoneum	UBERON:0002358	62.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	62.55	gold quality
smooth muscle tissue	UBERON:0001135	61.65	gold quality
adipose tissue of abdominal region	UBERON:0007808	61.47	gold quality
embryo	UBERON:0000922	60.88	silver quality
diaphragm	UBERON:0001103	58.82	gold quality
rectum	UBERON:0001052	56.97	gold quality
colonic epithelium	UBERON:0000397	56.19	gold quality
mucosa of transverse colon	UBERON:0004991	56.01	gold quality
mucosa of stomach	UBERON:0001199	55.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	55.55	gold quality
layer of synovial tissue	UBERON:0007616	54.84	silver quality
endothelial cell	CL:0000115	54.56	gold quality
tendon	UBERON:0000043	54.46	silver quality
biceps brachii	UBERON:0001507	54.04	gold quality
skin of hip	UBERON:0001554	54.00	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.32

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
BMP4	Unknown
COL10A1	Unknown
GDF5	Unknown
NKX3-2
PAX3	Repression
RUNX2	Repression
SOX9	Activation
WNT5A	Unknown

JASPAR motifs

Motif	Name	Family
MA0122.2	NKX3-2	NK

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): HOXA2, MEOX1, MEOX2, NKX3-1, NKX3-2, PAX1, PAX9, SOX9, TCF15

miRNA regulators (miRDB)

53 targeting NKX3-2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-6891-5P	99.98	66.53	1372
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-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 11)

• Data show that Meox1 activates the Bapx1 promoter in a dose-dependent manner and that this activity is enhanced in the presence of Pax1 and/or Pax9. (PMID:15024065)
• NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans (PMID:20004766)
• Data show that IkappaB kinase beta (IKKbeta) can be activated in the nucleus by Nkx3.2 in the absence of exogenous IKK-activating signals, allowing constitutive nuclear degradation of IkappaB-alpha. (PMID:21606193)
• Ihh-induced Nkx3.2 degradation requires Wnt5a, which is capable of triggering Nkx3.2 degradation (PMID:22507129)
• Our findings indicate that BAPX-1/NKX-3.2 is a molecular switch that is involved in controlling the hypertrophic phenotype of the postdevelopmental (OA) articular chondrocyte. (PMID:26245691)
• PI3K-mediated suppression of Nkx3.2 in chondrocytes plays a role in the control of cartilage hypertrophy during skeletal development in vertebrates. (PMID:26363466)
• post-translational modification of Nkx3.2 employing HDAC9-PIASy-RNF4 axis plays a crucial role in controlling chondrocyte viability and hypertrophic maturation during skeletal development in vertebrates. (PMID:27312341)
• Bapx1 indicates poor prognosis for gastric cancer patients by promoting tumor migration and invasion via TGF-beta-induced epithelial-mesenchymal transition. (PMID:28315334)
• A novel NKX3-2 mutation causes perinatal lethal spondylo-megaepiphyseal-metaphyseal dysplasia. (PMID:29704686)
• NKL homeobox gene NKX2-5 was activated by NKX3-2 in CCRF-CEM and by FOXG1 in PEER, representing mutually inhibitory activators of this translocated oncogene. (PMID:29746601)
• BMP7 increases protein synthesis in SW1353 cells and determines rRNA levels in a NKX3-2-dependent manner. (PMID:35139106)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	nkx3-2	ENSDARG00000037639
mus_musculus	Nkx3-2	ENSMUSG00000049691
rattus_norvegicus	Nkx3-2	ENSRNOG00000076257
drosophila_melanogaster	NK7.1	FBGN0024321
drosophila_melanogaster	HGTX	FBGN0040318
drosophila_melanogaster	scro	FBGN0287186
caenorhabditis_elegans	ceh-9	WBGENE00000434
caenorhabditis_elegans		WBGENE00000447
caenorhabditis_elegans		WBGENE00000450
caenorhabditis_elegans		WBGENE00000584

Paralogs (13): NKX2-3 (ENSG00000119919), NKX2-4 (ENSG00000125816), NKX2-2 (ENSG00000125820), NKX2-8 (ENSG00000136327), NKX2-1 (ENSG00000136352), NKX6-2 (ENSG00000148826), NKX6-1 (ENSG00000163623), NKX6-3 (ENSG00000165066), NKX3-1 (ENSG00000167034), NKX2-6 (ENSG00000180053), NKX2-5 (ENSG00000183072), NKX1-2 (ENSG00000229544), NKX1-1 (ENSG00000235608)

Protein

Protein identifiers

Homeobox protein Nkx-3.2 — P78367 (reviewed: P78367)

Alternative names: Bagpipe homeobox protein homolog 1, Homeobox protein NK-3 homolog B

All UniProt accessions (1): P78367

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor that acts as a negative regulator of chondrocyte maturation. PLays a role in distal stomach development; required for proper antral-pyloric morphogenesis and development of antral-type epithelium. In concert with GSC, defines the structural components of the middle ear; required for tympanic ring and gonium development and in the regulation of the width of the malleus.

Subcellular location. Nucleus.

Tissue specificity. Expressed at highest levels in cartilage, bone (osteosarcoma) and gut (small intestine and colon), whereas moderate expression is seen in trachea and brain. Expressed in visceral mesoderm and embryonic skeleton.

Disease relevance. Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) [MIM:613330] A skeletal dysplasia characterized by disproportionate short stature with a short and stiff neck and trunk, relatively long limbs that may show flexion contractures of the distal joints, delayed and impaired ossification of the vertebral bodies, the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones, and numerous pseudoepiphyses of the short tubular bones in hands and feet. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the NK-3 homeobox family.

RefSeq proteins (1): NP_001180* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR020479	HD_metazoa	Domain
IPR050394	Homeobox_NK-like	Family

Pfam: PF00046

UniProt features (8 total): compositionally biased region 4, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78367-F1	60.96	0.20

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8939902	Regulation of RUNX2 expression and activity

MSigDB gene sets: 224 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PANCREAS_DEVELOPMENT, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_DIGESTIVE_SYSTEM_DEVELOPMENT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (18): skeletal system development (GO:0001501), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), determination of left/right symmetry (GO:0007368), cell differentiation (GO:0030154), pancreas development (GO:0031016), negative regulation of chondrocyte differentiation (GO:0032331), middle ear morphogenesis (GO:0042474), negative regulation of apoptotic process (GO:0043066), spleen development (GO:0048536), animal organ formation (GO:0048645), skeletal system morphogenesis (GO:0048705), embryonic skeletal system development (GO:0048706), intestinal epithelial cell development (GO:0060576), negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), animal organ development (GO:0048513), digestive system development (GO:0055123)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transcriptional regulation by RUNX2	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
system development	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
animal organ morphogenesis	2
skeletal system development	2
regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	1
determination of bilateral symmetry	1
left/right pattern formation	1
cellular developmental process	1
animal organ development	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
ear morphogenesis	1
embryonic morphogenesis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
hematopoietic or lymphoid organ development	1
anatomical structure formation involved in morphogenesis	1
chordate embryonic development	1
columnar/cuboidal epithelial cell development	1
intestinal epithelial cell differentiation	1
negative regulation of DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
anatomical structure development	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1

Protein interactions and networks

STRING

966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NKX3-2	TCF21	O43680	789
NKX3-2	HAND2	P61296	719
NKX3-2	MSC	O60682	679
NKX3-2	PAX1	P15863	670
NKX3-2	SALL1	Q9NSC2	650
NKX3-2	SOX6	P35712	641
NKX3-2	SMAD4	Q13485	631
NKX3-2	PAX9	P55771	630
NKX3-2	TCOF1	Q13428	621
NKX3-2	BARX1	Q9HBU1	609
NKX3-2	SOX9	P48436	603
NKX3-2	SHH	Q15465	598
NKX3-2	EYA1	Q99502	548
NKX3-2	RUNX2	Q13950	529
NKX3-2	SOX5	P35711	525

IntAct

4 interactions, top by confidence:

A	B	Type	Score
NKX3-2	POU6F2	psi-mi:“MI:0915”(physical association)	0.560
NKX3-2	POU6F2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): NKX3-2 (Two-hybrid), NKX3-2 (Affinity Capture-RNA), NKX3-2 (Positive Genetic), NKX3-2 (Reconstituted Complex), NKX3-2 (Reconstituted Complex), SMAD1 (Reconstituted Complex), SMAD4 (Reconstituted Complex), HDAC1 (Reconstituted Complex), HDAC1 (Affinity Capture-Western), SIN3A (Affinity Capture-Western), RBBP7 (Affinity Capture-Western), RBBP4 (Affinity Capture-Western), SMAD1 (Affinity Capture-Western), SMAD4 (Affinity Capture-Western)

ESM2 similar proteins: A1YF08, A1YFD8, A1YFY3, A1YG85, A2D4P8, A2D5I1, A2RU54, A2T6X6, A2T756, A6NCS4, O15522, O35137, O43763, O70584, P09066, P10284, P10628, P17483, P19622, P23683, P31275, P31276, P42580, P43687, P43688, P49640, P50207, P50223, P52945, P52946, P52947, P63156, P63157, P70061, P70118, P78367, P82976, P97503, Q14549, Q4LAL6

Diamond homologs: A1YF16, A1YG93, A2RU54, A2T764, A6NCS4, A6NHT5, A8XJD0, F1R2J1, O02786, O35762, O35767, O43711, O43763, O55144, O57601, O70218, O88181, O93366, O93367, O93590, P13297, P19601, P22809, P23410, P26797, P28360, P28361, P28362, P31314, P35548, P35993, P42581, P42582, P42583, P43345, P43687, P50223, P52952, P52953, P56407

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	1
Uncertain significance	89
Likely benign	59
Benign	10

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
2425047	NC_000004.11:g.(?13371500)(13546038_?)del	Pathogenic
2854529	NM_001189.4(NKX3-2):c.59del (p.Lys20fs)	Pathogenic
3620145	NM_001189.4(NKX3-2):c.295G>T (p.Glu99Ter)	Pathogenic
3630732	NM_001189.4(NKX3-2):c.362dup (p.Ser122fs)	Pathogenic
4806727	NM_001189.4(NKX3-2):c.304G>T (p.Glu102Ter)	Pathogenic
7491	NM_001189.4(NKX3-2):c.337dup (p.Ala113fs)	Pathogenic
7492	NM_001189.4(NKX3-2):c.336_337delinsT (p.Ala113fs)	Pathogenic
7493	NM_001189.4(NKX3-2):c.104_110del (p.Ala35fs)	Pathogenic
1702471	NM_001189.4(NKX3-2):c.94_100dup (p.Pro34fs)	Likely pathogenic

SpliceAI

412 predictions. Top by Δscore:

Variant	Effect	Δscore
4:13542537:CCCGG:C	acceptor_gain	1.0000
4:13542538:CCGG:C	acceptor_gain	1.0000
4:13542539:C:T	acceptor_gain	1.0000
4:13542539:CGG:C	acceptor_gain	1.0000
4:13542540:G:T	acceptor_gain	1.0000
4:13542541:G:C	acceptor_gain	0.9900
4:13542541:G:GC	acceptor_gain	0.9900
4:13542527:GCC:G	acceptor_loss	0.9800
4:13542529:C:CA	acceptor_loss	0.9800
4:13542530:T:C	acceptor_loss	0.9800
4:13543943:GCAGA:G	donor_loss	0.9800
4:13543944:CAGA:C	donor_loss	0.9800
4:13543945:AGACC:A	donor_loss	0.9800
4:13543946:GACC:G	donor_loss	0.9800
4:13543948:CC:C	donor_loss	0.9800
4:13542525:TCGC:T	acceptor_gain	0.9700
4:13542526:CGC:C	acceptor_gain	0.9700
4:13542526:CGCC:C	acceptor_gain	0.9700
4:13542527:GC:G	acceptor_gain	0.9700
4:13542528:CC:C	acceptor_gain	0.9700
4:13542529:C:CC	acceptor_gain	0.9700
4:13543993:T:TA	donor_gain	0.9700
4:13542524:GTCGC:G	acceptor_gain	0.9600
4:13542869:G:C	donor_gain	0.9600
4:13542539:C:CT	acceptor_loss	0.9500
4:13542812:C:A	donor_gain	0.9500
4:13543949:C:G	donor_loss	0.9500
4:13542525:TCGCC:T	acceptor_gain	0.9400
4:13542526:CGCCT:C	acceptor_gain	0.9400
4:13542527:GCCTG:G	acceptor_gain	0.9400

AlphaMissense

2109 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:13542208:G:T	R263S	1.000
4:13542209:C:A	K262N	1.000
4:13542209:C:G	K262N	1.000
4:13542215:C:A	K260N	1.000
4:13542215:C:G	K260N	1.000
4:13542216:T:A	K260M	1.000
4:13542217:T:C	K260E	1.000
4:13542220:A:G	Y259H	1.000
4:13542223:G:T	R258S	1.000
4:13542226:G:T	R257S	1.000
4:13542227:G:C	N256K	1.000
4:13542227:G:T	N256K	1.000
4:13542228:T:A	N256I	1.000
4:13542228:T:C	N256S	1.000
4:13542228:T:G	N256T	1.000
4:13542229:T:C	N256D	1.000
4:13542229:T:G	N256H	1.000
4:13542230:C:A	Q255H	1.000
4:13542230:C:G	Q255H	1.000
4:13542231:T:G	Q255P	1.000
4:13542233:G:C	F254L	1.000
4:13542233:G:T	F254L	1.000
4:13542234:A:C	F254C	1.000
4:13542234:A:G	F254S	1.000
4:13542235:A:C	F254V	1.000
4:13542235:A:G	F254L	1.000
4:13542235:A:T	F254I	1.000
4:13542236:C:A	W253C	1.000
4:13542236:C:G	W253C	1.000
4:13542238:A:G	W253R	1.000

dbSNP variants (sampled 300 via entrez): RS1000067599 (4:13541688 T>G), RS1000099954 (4:13541883 C>T), RS1000457376 (4:13548431 A>G), RS10007259 (4:13545489 T>C), RS1001093555 (4:13543232 C>G), RS1001336809 (4:13547767 G>A), RS1001633559 (4:13541920 T>C), RS1001796463 (4:13547715 G>A), RS1001851297 (4:13541018 T>C,G), RS1001967347 (4:13540736 G>A), RS1002392155 (4:13547521 C>T), RS1002468413 (4:13546183 T>C), RS1002762004 (4:13545774 T>TA), RS1003072585 (4:13545114 C>T), RS1003105124 (4:13545350 G>C)

Disease associations

OMIM: gene MIM:602183 | disease phenotypes: MIM:613330

GenCC curated gene-disease

Disease	Classification	Inheritance
spondylo-megaepiphyseal-metaphyseal dysplasia	Definitive	Autosomal recessive

Mondo (2): spondylo-megaepiphyseal-metaphyseal dysplasia (MONDO:0013228), connective tissue disorder (MONDO:0003900)

Orphanet (1): Spondylo-megaepiphyseal-metaphyseal dysplasia (Orphanet:228387)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000470	Short neck
HP:0000768	Pectus carinatum
HP:0000773	Short ribs
HP:0000946	Hypoplastic ilia
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001371	Flexion contracture
HP:0001518	Small for gestational age
HP:0001538	Protuberant abdomen
HP:0001762	Talipes equinovarus
HP:0001847	Long hallux
HP:0002650	Scoliosis
HP:0002751	Kyphoscoliosis
HP:0002812	Coxa vara
HP:0002827	Hip dislocation
HP:0002857	Genu valgum
HP:0002866	Hypoplastic iliac wing
HP:0002970	Genu varum
HP:0003025	Metaphyseal irregularity
HP:0003316	Butterfly vertebrae
HP:0003418	Back pain
HP:0003521	Disproportionate short-trunk short stature
HP:0003577	Congenital onset
HP:0004288	Pseudoepiphyses of hand bones
HP:0005659	Thoracic kyphoscoliosis

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002312_4	Periodontal disease-related phenotype (Socransky)	1.000000e-06
GCST002312_7	Periodontal disease-related phenotype (Socransky)	4.000000e-06
GCST009391_1098	Metabolite levels	1.000000e-06
GCST009391_1886	Metabolite levels	8.000000e-06
GCST009391_190	Metabolite levels	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0010447	3-hydroxyanthranilic acid measurement
EFO:0010414	triacylglycerol 52:2 measurement
EFO:0010482	gamma-aminoisobutyric acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
C567639	Spondylo-Megaepiphyseal-Metaphyseal Dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Valproic Acid	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
GSK-2816126	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Estradiol	decreases expression	1
Silicon Dioxide	decreases expression	1
Dihydrotestosterone	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Triclosan	increases expression	1
Cadmium Chloride	decreases expression	1
Zinc Sulfate	increases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT01093911	PHASE1	COMPLETED	Safety Study of CDP7657 in Healthy Volunteers and Patients With Systemic Lupus Erythematosus (SLE)
NCT01764594	PHASE1	COMPLETED	Safety Study of CDP7657 in Patients With Systemic Lupus Erythematosus
NCT02392130	PHASE1	COMPLETED	A Clinical Trial to Assess the Potential of LEO 130852A Gel to Reduce Steroid Induced Skin Atrophy on Healthy Skin
NCT03337165	PHASE1	COMPLETED	Autologous Tolerogenic Dendritic Cells for Treatment of Patients With Rheumatoid Arthritis
NCT03929120	PHASE1	COMPLETED	Allogeneic Bone Marrow Mesenchymal Stem Cells for Patients With Interstitial Lung Disease (ILD) & Connective Tissue Disorders (CTD)
NCT01424033	PHASE2/PHASE3	TERMINATED	A Clinical Trial for CTD-ILD Treatment
NCT04915482	PHASE2/PHASE3	UNKNOWN	TPO-RAs Combined With Anti-CD20 Antibody in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT06574581	PHASE1/PHASE2	RECRUITING	ADSCs Therapy in Patients With CTD-ILD
NCT00001330	Not specified	COMPLETED	Study of Silicone-Associated Connective Tissue Diseases
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00001978	Not specified	TERMINATED	Determination of Kidney Function
NCT00076830	Not specified	COMPLETED	Evaluation and Treatment of Patients With Connective Tissue Disease
NCT00341679	Not specified	COMPLETED	Studies of the Natural History and Pathogenesis of Autoimmune/Connective Tissue Diseases
NCT00470327	Not specified	RECRUITING	A Study of the Natural Progression of Interstitial Lung Disease (ILD)
NCT00491309	Not specified	UNKNOWN	Exercise and Respiratory Therapy in Patients With Rheumatoid Arthritis / Collagenosis and Pulmonary Hypertension