SHOX

Summary

SHOX (SHOX homeobox, HGNC:10853) is a protein-coding gene on chromosome Xp22.33 and Yp11.32, encoding Short stature homeobox protein (O15266). Transcription factor that controls fundamental aspects of growth.

This gene belongs to the paired homeobox family and is located in the pseudoautosomal region 1 (PAR1) of X and Y chromosomes. Defects in this gene are associated with idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients. This gene is highly conserved across species from mammals to fish to flies. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 6473 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Leri-Weill dyschondrosteosis (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 223 total — 28 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 76
• MANE Select transcript: NM_000451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10853
Approved symbol	SHOX
Name	SHOX homeobox
Location	Xp22.33 and Yp11.32
Locus type	gene with protein product
Status	Approved
Aliases	PHOG, GCFX, SS, SHOXY, SHOX1
Ensembl gene	ENSG00000185960
Ensembl biotype	protein_coding
OMIM	312865, 400020
Entrez	6473

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000334060, ENST00000381575, ENST00000381578, ENST00000686671

RefSeq mRNA: 2 — MANE Select: NM_000451 NM_000451, NM_006883

CCDS: CCDS14106, CCDS14107

Canonical transcript exons

ENST00000686671 — 5 exons

Exon	Start	End
ENSE00001334962	640999	641087
ENSE00003459973	640821	640878
ENSE00003491713	634618	634826
ENSE00003926768	644391	651584
ENSE00003930120	630791	631174

Expression profiles

Bgee: expression breadth broad, 31 present calls, max score 80.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2443 / max 116.5947, expressed in 40 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195316	0.2443	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	80.53	gold quality
subcutaneous adipose tissue	UBERON:0002190	59.35	gold quality
sural nerve	UBERON:0015488	57.65	gold quality
muscle of leg	UBERON:0001383	53.12	gold quality
gastrocnemius	UBERON:0001388	52.64	gold quality
adipose tissue	UBERON:0001013	51.59	gold quality
tibial artery	UBERON:0007610	50.93	gold quality
popliteal artery	UBERON:0002250	50.92	gold quality
skeletal muscle tissue	UBERON:0001134	50.01	gold quality
colonic epithelium	UBERON:0000397	49.30	gold quality
stromal cell of endometrium	CL:0002255	48.86	gold quality
bone marrow cell	CL:0002092	47.99	gold quality
skin of leg	UBERON:0001511	47.22	gold quality
duodenum	UBERON:0002114	46.80	silver quality
muscle tissue	UBERON:0002385	46.46	gold quality
hindlimb stylopod muscle	UBERON:0004252	46.01	gold quality
leukocyte	CL:0000738	43.49	gold quality
monocyte	CL:0000576	43.09	gold quality
bone marrow	UBERON:0002371	42.55	gold quality
zone of skin	UBERON:0000014	42.35	gold quality
omental fat pad	UBERON:0010414	41.89	gold quality
mucosa of transverse colon	UBERON:0004991	41.66	silver quality
thoracic mammary gland	UBERON:0005200	40.75	gold quality
cortical plate	UBERON:0005343	40.67	gold quality
transverse colon	UBERON:0001157	40.52	silver quality
rectum	UBERON:0001052	40.35	gold quality
placenta	UBERON:0001987	40.14	gold quality
primary visual cortex	UBERON:0002436	40.05	gold quality
tibial nerve	UBERON:0001323	39.62	gold quality
colon	UBERON:0001155	39.04	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ACAN	Unknown
FGFR3	Activation
NPPB	Activation

JASPAR motifs

Motif	Name	Family
MA0630.1	SHOX	Paired-related HD factors
MA0630.2	SHOX	Paired-related HD factors

JASPAR matrix evidence (PMIDs): PMID:23332764

Upstream regulators (CollecTRI, top): HOXA9

miRNA regulators (miRDB)

82 targeting SHOX, 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-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776

Literature-anchored findings (GeneRIF, showing 40)

• point mutations in dyschondrosteosis (PMID:11403039)
• role of SHOX defects in idiopathic short stature and skeletal dysplasias (PMID:11716161)
• Product is a sequence-specific DNA-binding protein which acts as a transcriptional activator. (PMID:11751690)
• SHOX intragenic microsatellite might be a useful molecular marker to detect Turner syndrome and when skeletal disproportion is associated with short stature a significant proportion of patients is found to have a single SHOX allele (PMID:11874178)
• mesomelic skeletal features such as Langer mesomelic dysplasia and LWDC are primarily caused by the SHOX dosage effect (PMID:11889214)
• Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. (PMID:11889216)
• Point mutations and large deletions cause dyschondrosteosis (Leri-Weill syndrome). (PMID:11891678)
• Crossover clustering and rapid decay of disequilibrium linkage in the Xp/Yp pseudoautosomal gene was studied. (PMID:12089524)
• SHOX deletion is aasociated with short stature (PMID:12784295)
• functional SHOX protein levels are regulated by a combination of transcriptional and translational control mechanisms (PMID:12960152)
• SHOX is a major growth gene and that mutations are associated with a broad range of phenotype (PMID:14513875)
• chromosomal rearrangement resulted in the deletion of SHOX but not SRY. (PMID:14981722)
• Gonadal estrogens have a deleterious effect on pubertal growth in SHOX haploinsufficiency. (PMID:15118270)
• SHOX is a regulator of cellular proliferation and viability (PMID:15145945)
• Nuclear localization is a mechanistic basis for SHOX-related diseases. (PMID:15173321)
• a compound heterozygote with two independent deletions of Xpter-Xp22.12 including SHOX (one inherited and one arising from a de novo event) results in Langer mesomelic dwarfism (PMID:15214013)
• SHOX may play role in chondrocyte function in growth plate. (PMID:15292358)
• Height is reduced in Turner syndrome due to haploinsufficiency of SHOX gene, an Xp chromosome gene that escapes inactivation. (PMID:15529627)
• we show that, although the identified deletions vary in size, the vast majority (73%) of patients tested share a distinct proximal deletion breakpoint. (PMID:15931595)
• nine different amino acid exchanges in the homeodomain of SHOX patients with idiopathic short stature and Leri-Weill dyschondrosteosis (PMID:15931687)
• findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development (PMID:16175500)
• 54 SHOX anomalies were observed, including 42 (68%) in the dyschondrosteosis group and 12 (15%) in the idiopathic short stature (ISS) group. (PMID:16597678)
• Review on clinical and molecular data associated SHOX gene defects. (PMID:16807223)
• In contrast to previous reports, Leri-Weill dyschondrosteosis-causing SHOX deletions are very heterogeneous. (PMID:16826534)
• Pseudoautosomal region 1 deletions downstream of SHOX are the most frequent defect in a Spanish cohort of Leri-Weill dyschondrosteosis (LWD) probands. (PMID:16941489)
• Screening of 1608 unrelated individuals with sporadic or familial short stature revealed SHOX mutations or deletions in 68 individuals (4.2%): complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). (PMID:17182655)
• Long-range conserved non-coding SHOX sequences regulate expression in developing chicken limb and are associated with short stature phenotypes in human patients. (PMID:17200153)
• patients with SHOX mutations present a broad phenotypic variability; SHOX mutations are very frequent in Leri-Weill dyschondrosteosis (89%), in opposition to idiopathic short stature (3.2%) in our cohort (PMID:17201812)
• BNP represents a direct target of SHOX. (PMID:17881654)
• SHOX mutations may have a role in development of short stature (PMID:17911654)
• Homozygous deletion of the 3’ enhancer of the SHOX gene causes Langer mesomelic dysplasia. (PMID:17935511)
• skeletal dysplasia in both mother and son is allelic with LWD and LMD and results from a novel misexpression of SHOX (PMID:17994562)
• SHOX gene alterations may play a role in the determinism of growth impairment in short children with muscular dystrophies. (PMID:18059093)
• Cryptic intragenic deletions account for a small fraction of Leri-Weill dyschondrosteosis. (PMID:18322641)
• SHOX haploinsufficiency is an important cause of short stature in a diversity of clinical conditions and it explains 2/3 of short stature observed in Turner syndrome (PMID:18797583)
• increased SHOX expression was demonstrated in idiopathic scoliosis (tall stature) and congenital scoliosis (PMID:19016538)
• Patients with SHOX deficiency receive similar final height benefit from GH treatment to those with Turner syndrome. (PMID:19188742)
• Enhancer deletions in the SHOX gene region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome. (PMID:19578035)
• we summarize the genetic and clinical features of the various SHOX haploinsufficiency-associated disorders. (PMID:19724992)
• SHOX upstream deletions occur at a lower frequency because of the structural organization of this genomic region. (PMID:19997128)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
danio_rerio	shox	ENSDARG00000025891

Paralogs (50): ARX (ENSG00000004848), PAX6 (ENSG00000007372), PAX7 (ENSG00000009709), ALX4 (ENSG00000052850), GSC2 (ENSG00000063515), PITX1 (ENSG00000069011), PAX2 (ENSG00000075891), RHOXF1 (ENSG00000101883), CRX (ENSG00000105392), EVX1 (ENSG00000106038), PAX4 (ENSG00000106331), NOBOX (ENSG00000106410), PITX3 (ENSG00000107859), PHOX2B (ENSG00000109132), OTX1 (ENSG00000115507), PRRX1 (ENSG00000116132), VSX2 (ENSG00000119614), ESX1 (ENSG00000123576), PAX8 (ENSG00000125618), PAX1 (ENSG00000125813), RHOXF2 (ENSG00000131721), GSC (ENSG00000133937), RAX (ENSG00000134438), PAX3 (ENSG00000135903), ALX3 (ENSG00000156150), HESX1 (ENSG00000163666), PITX2 (ENSG00000164093), UNCX (ENSG00000164853), PHOX2A (ENSG00000165462), OTX2 (ENSG00000165588), DRGX (ENSG00000165606), PRRX2 (ENSG00000167157), SHOX2 (ENSG00000168779), OTP (ENSG00000171540), RAX2 (ENSG00000173976), EVX2 (ENSG00000174279), PROP1 (ENSG00000175325), ISX (ENSG00000175329), ALX1 (ENSG00000180318), MIXL1 (ENSG00000185155)

Protein

Protein identifiers

Short stature homeobox protein — O15266 (reviewed: O15266)

Alternative names: Pseudoautosomal homeobox-containing osteogenic protein, Short stature homeobox-containing protein

All UniProt accessions (1): O15266

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that controls fundamental aspects of growth. Directly activates NPPB transcription in osteogenic cells. Preferentially binds DNA elements with the sequence 5’-TAATNNNATTA-3’, possibly as a homodimer.

Subunit / interactions. May form homodimers.

Subcellular location. Nucleus.

Tissue specificity. Expressed at high levels in bone marrow fibroblasts and trabecular bone cells. Also detected in placenta. Expressed in bone growth plate, with high levels in the zone of hypertrophic chondrocytes and lower expression in proliferating and resting chondrocytes (at protein level). in the knee cartilage, tends to be expressed at higher levels in men, compared to women. Expressed in skeletal muscle, placenta, pancreas, heart and bone marrow fibroblasts. Expressed at high levels in bone marrow fibroblasts. Also expressed in fetal kidney and skeletal muscle.

Disease relevance. Leri-Weill dyschondrosteosis (LWD) [MIM:127300] Dominantly inherited skeletal dysplasia characterized by moderate short stature predominantly because of short mesomelic limb segments. It is often associated with the Madelung deformity of the wrist, comprising bowing of the radius and dorsal dislocation of the distal ulna. The disease is caused by variants affecting the gene represented in this entry. Langer mesomelic dysplasia (LMD) [MIM:249700] Autosomal recessive rare skeletal dysplasia characterized by severe short stature owing to shortening and maldevelopment of the mesomelic and rhizomelic segments of the limbs. Associated malformations are rarely reported and intellect is normal in all affected subjects reported to date. The disease is caused by variants affecting the gene represented in this entry. Short stature, idiopathic, X-linked (ISS) [MIM:300582] A condition defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, genetically relevant population, in the absence of specific causative disorders. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. It is hypothesized that SHOX may contribute to the difference in height between men and women. Although SHOX gene is located in the pseudoautosomal region PAR1 of X and Y chromosomes and is assumed to escape chromosome X inactivation, it is thought that SHOX gene expression from inactivated X chromosome is nevertheless lower than that from active X or Y chromosomes. Small, but persistent sex difference in SHOX expression dosage may lead to the variation in the sex steroid-independent childhood growth function, thereby yielding the sex difference in height.

Similarity. Belongs to the paired homeobox family. Bicoid subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O15266-1	SHOXA	yes
O15266-2	SHOXB

RefSeq proteins (2): NP_000442, NP_006874 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000047	HTH_motif	Conserved_site
IPR001356	HD	Domain
IPR003654	OAR_dom	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR052631	Paired_homeobox_Bicoid	Family

Pfam: PF00046, PF03826

UniProt features (22 total): sequence variant 10, mutagenesis site 3, short sequence motif 3, region of interest 2, chain 1, DNA-binding region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15266-F1	63.90	0.24

Functional residue map

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

Post-translational modifications (1): 106

Mutagenesis-validated functional residues (3):

Position	Phenotype
106	strong decrease in transcriptional activity.
194–292	loss of transcriptional activity. no effect on nuclear localization.
271–292	decreased transcriptional activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 202 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_SEQUENCE_SPECIFIC_DNA_BINDING, chrXp22, chrYp11, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOMF_DNA_BINDING_TRANSCRIPTION_ACTIVATOR_ACTIVITY, KRAS.600.LUNG.BREAST_UP.V1_UP, KRAS.LUNG.BREAST_UP.V1_UP, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, MIR616_5P, MIR371B_5P, MIR373_5P, MIR3658, MIR186_5P

GO Biological Process (4): skeletal system development (GO:0001501), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (6): DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular anatomical structure	2
system development	1
regulation of DNA-templated transcription	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHOX	ARSL	P51690	915
SHOX	CD99	P14209	777
SHOX	STS	P08842	762
SHOX	CSF2RA	P15509	745
SHOX	SRY	Q05066	716
SHOX	SOX3	P35714	688
SHOX	ASMT	P46597	646
SHOX	GHR	P10912	641
SHOX	NPPC	P23582	641
SHOX	ANOS1	P23352	639
SHOX	PLCXD1	Q9NUJ7	639
SHOX	FGFR3	P22607	631
SHOX	ASMTL	O95671	628
SHOX	IL3RA	P26951	624
SHOX	VCX3A	Q9NNX9	622

IntAct

10 interactions, top by confidence:

A	B	Type	Score
SOX5	SHOX	psi-mi:“MI:0915”(physical association)	0.510
SOX6	SHOX	psi-mi:“MI:0915”(physical association)	0.510
SHOX	SOX6	psi-mi:“MI:0915”(physical association)	0.510
SHOX	Sox5	psi-mi:“MI:0915”(physical association)	0.370
Sox6	SHOX	psi-mi:“MI:0915”(physical association)	0.370
SHOX	SHOX	psi-mi:“MI:0915”(physical association)	0.370
SHOX	PBX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): SHOX (Two-hybrid), SHOX (Two-hybrid), SHOX (Two-hybrid), SHOX (Two-hybrid), C17orf70 (Affinity Capture-MS), KLHDC8B (Affinity Capture-MS), PKNOX1 (Affinity Capture-MS), PBX2 (Affinity Capture-MS), PBX1 (Affinity Capture-MS)

ESM2 similar proteins: B0W1V2, B0X9H6, B3DM47, B4H4H5, B5DLV1, E7FDX5, G5EC89, O15266, O22300, O35317, O35984, O73673, O76762, O77215, O93366, P05527, P10035, P10181, P22809, P23459, P29552, P39021, P40424, P40425, P40426, P41778, P49925, P53772, P53773, P56224, Q05007, Q05192, Q07961, Q1KKY1, Q1KL13, Q24648, Q27355, Q28ZA9, Q4V5A3, Q4VYR7

Diamond homologs: A1A546, A1YEV8, A1YG25, A2T711, A6NJT0, A6NNA5, A6YP92, G5EC89, G5EDS1, L8E946, O08934, O09113, O14813, O15266, O18381, O35085, O35137, O35602, O35690, O35750, O42115, O42201, O42250, O42356, O42357, O42358, O42477, O42567, O60902, O70137, O73917, O95076, O97039, P0DMV5, P23759, P23760, P24610, P26367, P26630, P29506

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	SHOX	phosphorylation
SHOX	“up-regulates quantity by expression”	NPPB	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	28
Likely pathogenic	15
Uncertain significance	108
Likely benign	16
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1175841	GRCh37/hg19 Xp22.33(chrX:585079-619564)x1	Pathogenic
1184887	NM_000451.4(SHOX):c.99del (p.Thr34fs)	Pathogenic
1256555	NM_000451.4(SHOX):c.518G>A (p.Arg173His)	Pathogenic
1676140	NM_000451.4(SHOX):c.40C>T (p.Gln14Ter)	Pathogenic
1686189	NM_000451.4(SHOX):c.463G>C (p.Gly155Arg)	Pathogenic
1686190	NM_000451.4(SHOX):c.670G>A (p.Ala224Thr)	Pathogenic
1686191	NM_000451.4(SHOX):c.673CACCCGCACCTG[1] (p.225HPHL[1])	Pathogenic
1686193	NM_000451.4(SHOX):c.805del (p.Ser269fs)	Pathogenic
191363	NM_006883.2(SHOX):c.-645_-644insGTT	Pathogenic
2428621	NM_000451.4(SHOX):c.582C>A (p.Cys194Ter)	Pathogenic
265858	NM_000451.4(SHOX):c.528G>C (p.Glu176Asp)	Pathogenic
29994	NM_000451.4(SHOX):c.508G>C (p.Ala170Pro)	Pathogenic
29995	NM_000451.4(SHOX):c.509C>A (p.Ala170Asp)	Pathogenic
3024697	GRCh37/hg19 Xp22.33(chrX:591633-595561)x1	Pathogenic
374328	NM_000451.4(SHOX):c.544+1G>A	Pathogenic
448378	NM_000451.4(SHOX):c.712_714delinsAG (p.Tyr238fs)	Pathogenic
4535998	NC_000023.10:g.(595562_601555)(612320?)del	Pathogenic
66087	NC_000024.9:g.730550_778092del	Pathogenic
9872	NM_000451.4(SHOX):c.583C>T (p.Arg195Ter)	Pathogenic
9873	NM_000451.4(SHOX):c.597C>G (p.Tyr199Ter)	Pathogenic
9874	NG_009385.2:g.(?5001)(40068_?)del	Pathogenic
9877	NM_000451.4(SHOX):c.181del (p.Glu61fs)	Pathogenic
9878	NM_000451.4(SHOX):c.517C>T (p.Arg173Cys)	Pathogenic
9880	NM_000451.4(SHOX):c.728dup (p.Pro244fs)	Pathogenic
9881	NM_000451.4(SHOX):c.352_353dup (p.Arg119fs)	Pathogenic
9882	NM_000451.4(SHOX):c.304G>T (p.Glu102Ter)	Pathogenic
988349	NM_000451.4(SHOX):c.605del (p.Met202fs)	Pathogenic
9884	NC_000023.11:g.(651585_658784)_(659412_1759412)del	Pathogenic
1224466	NM_000451.4(SHOX):c.615_616insAA (p.Arg206fs)	Likely pathogenic
1333444	NM_000451.4(SHOX):c.250G>T (p.Glu84Ter)	Likely pathogenic

SpliceAI

1113 predictions. Top by Δscore:

Variant	Effect	Δscore
X:634826:GGTAG:G	donor_loss	1.0000
X:634827:G:A	donor_loss	1.0000
X:634828:T:A	donor_loss	1.0000
X:640876:AAGG:A	donor_loss	1.0000
X:640879:GTGG:G	donor_loss	1.0000
X:640990:T:TA	acceptor_gain	1.0000
X:640991:G:A	acceptor_gain	1.0000
X:640994:CACAG:C	acceptor_loss	1.0000
X:640997:A:AG	acceptor_gain	1.0000
X:640998:G:GG	acceptor_gain	1.0000
X:640998:GGC:G	acceptor_gain	1.0000
X:641083:AACAG:A	donor_loss	1.0000
X:641085:CAGG:C	donor_loss	1.0000
X:641086:AG:A	donor_loss	1.0000
X:641087:GG:G	donor_loss	1.0000
X:624598:GCTTG:G	donor_gain	0.9900
X:631171:GAAG:G	donor_gain	0.9900
X:631173:AGGT:A	donor_loss	0.9900
X:631175:G:GG	donor_gain	0.9900
X:631175:GTA:G	donor_loss	0.9900
X:631176:T:A	donor_loss	0.9900
X:634613:C:CA	acceptor_gain	0.9900
X:634613:C:G	acceptor_gain	0.9900
X:634616:A:AG	acceptor_gain	0.9900
X:634616:AG:A	acceptor_gain	0.9900
X:634616:AGG:A	acceptor_gain	0.9900
X:634617:G:GG	acceptor_gain	0.9900
X:634617:GG:G	acceptor_gain	0.9900
X:634617:GGG:G	acceptor_gain	0.9900
X:634617:GGGA:G	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000029171 (X:628061 C>A,G), RS1000042924 (X:651107 T>TTTA), RS1000064881 (X:623458 AGAG>A), RS1000104276 (X:636977 C>A,G,T), RS1000115089 (X:623655 T>C), RS1000141591 (X:655883 A>G), RS1000213508 (X:646425 A>T), RS1000262983 (X:655570 C>A,G,T), RS1000478982 (X:632385 A>T), RS1000634703 (X:627336 T>C), RS1000689456 (X:659086 T>A), RS1000703798 (X:635878 G>A,C), RS1000719102 (X:635704 C>T), RS1000970292 (X:659276 G>A), RS1001122078 (X:622361 G>A)

Disease associations

OMIM: gene MIM:312865, MIM:400020 | disease phenotypes: MIM:249700, MIM:127300, MIM:300582

GenCC curated gene-disease

Disease	Classification	Inheritance
Leri-Weill dyschondrosteosis	Definitive	X-linked
Langer mesomelic dysplasia	Definitive	X-linked
SHOX-related short stature	Supportive	Autosomal dominant

Mondo (4): Langer mesomelic dysplasia (MONDO:0009588), Leri-Weill dyschondrosteosis (MONDO:0007481), SHOX-related short stature (MONDO:0010367), connective tissue disorder (MONDO:0003900)

Orphanet (3): Langer mesomelic dysplasia (Orphanet:2632), Léri-Weill dyschondrosteosis (Orphanet:240), SHOX-related short stature (Orphanet:314795)

HPO phenotypes

76 total (30 of 76 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000347	Micrognathia
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000944	Abnormal metaphysis morphology
HP:0001156	Brachydactyly
HP:0001191	Abnormal carpal morphology
HP:0001249	Intellectual disability
HP:0001387	Joint stiffness
HP:0001417	X-linked inheritance
HP:0001513	Obesity
HP:0001773	Short foot
HP:0001804	Hypoplastic fingernail
HP:0001831	Short toe
HP:0001832	Abnormal metatarsal morphology
HP:0002644	Abnormal pelvic girdle bone morphology
HP:0002650	Scoliosis
HP:0002673	Coxa valga
HP:0002683	Abnormal calvaria morphology
HP:0002762	Multiple exostoses
HP:0002818	Abnormal morphology of the radius
HP:0002823	Abnormal femur morphology
HP:0002857	Genu valgum
HP:0002938	Lumbar hyperlordosis
HP:0002967	Cubitus valgus
HP:0002970	Genu varum
HP:0002982	Tibial bowing
HP:0002983	Micromelia

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
C537267	Langer mesomelic dysplasia (supp.)
C564479	Short Stature, Idiopathic, X-Linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Resveratrol	affects cotreatment, decreases expression	2
deoxynivalenol	decreases expression	1
2-palmitoylglycerol	increases expression	1
Vorinostat	decreases expression	1
Cadmium	increases abundance, increases expression	1
Carmustine	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases abundance, increases expression	1

Cellosaurus cell lines

10 cell lines: 7 transformed cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A6C7	SEES3-1V human SHOX, clone1	Embryonic stem cell	Male
CVCL_A6C8	SEES3-1V human SHOX, clone2	Embryonic stem cell	Male
CVCL_A6C9	SEES3-1V human SHOX, clone3	Embryonic stem cell	Male
CVCL_DA82	GM20212	Transformed cell line	Female
CVCL_DA83	GM20213	Transformed cell line	Male
CVCL_DA84	GM20214	Transformed cell line	Female
CVCL_DA85	GM20215	Transformed cell line	Male
CVCL_DA86	GM20216	Transformed cell line	Female
CVCL_DA87	GM20217	Transformed cell line	Male
CVCL_DA88	GM20218	Transformed cell line	Female

Clinical trials (associated diseases)

91 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
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT07226089	PHASE3	RECRUITING	Comparison of Weekly Somatrogon to Daily Genotropin in Children Born Small for Gestational Age or With Idiopathic Short Stature.
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
NCT05305365	PHASE2	ACTIVE_NOT_RECRUITING	Study Assessing QBS72S For Treating Brain Metastases
NCT06016387	PHASE2	RECRUITING	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 Mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study
NCT02727803	PHASE2	RECRUITING	Personalized NK Cell Therapy in CBT
NCT05497804	PHASE2	ACTIVE_NOT_RECRUITING	Combination Treatment Therapy Approaches for the Treatment of High-Risk Multiple Myeloma, REACH Trial
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)
NCT01619761	PHASE1	UNKNOWN	NK Cells in Cord Blood Transplantation
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)
NCT03267888	PHASE1/PHASE2	COMPLETED	Pembrolizumab and Radiation Therapy in Patients With Relapsed or Refractory Multiple Myeloma
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