LHX9

Summary

LHX9 (LIM homeobox 9, HGNC:14222) is a protein-coding gene on chromosome 1q31.3, encoding LIM/homeobox protein Lhx9 (Q9NQ69). Involved in gonadal development.

This gene encodes a member of the LIM homeobox gene family of developmentally expressed transcription factors. The encoded protein contains a homeodomain and two cysteine-rich zinc-binding LIM domains involved in protein-protein interactions. The protein is highly similar to a mouse protein that causes gonadal agenesis when inactivated, suggesting a role in gonadal development. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 56956 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_020204

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14222
Approved symbol	LHX9
Name	LIM homeobox 9
Location	1q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143355
Ensembl biotype	protein_coding
OMIM	606066
Entrez	56956

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000367387, ENST00000367388, ENST00000367390, ENST00000367391, ENST00000475727, ENST00000561173, ENST00000606127, ENST00000615520

RefSeq mRNA: 4 — MANE Select: NM_020204 NM_001014434, NM_001370213, NM_001410927, NM_020204

CCDS: CCDS1393, CCDS30962, CCDS91139

Canonical transcript exons

ENST00000367387 — 5 exons

Exon	Start	End
ENSE00000959533	197919972	197920174
ENSE00000959534	197921304	197921659
ENSE00000959535	197927591	197927793
ENSE00001835531	197929002	197935478
ENSE00001869597	197917372	197917997

Expression profiles

Bgee: expression breadth broad, 84 present calls, max score 89.61.

FANTOM5 (CAGE): breadth broad, TPM avg 6.9194 / max 1872.9045, expressed in 354 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7531	6.0669	317
7535	0.2593	72
7530	0.2547	51
7536	0.1610	19
7534	0.0446	21
7533	0.0410	26
7528	0.0382	14
7532	0.0220	11
7537	0.0188	3
7529	0.0086	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	89.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.01	silver quality
ovary	UBERON:0000992	74.28	gold quality
left ovary	UBERON:0002119	73.88	gold quality
right ovary	UBERON:0002118	71.89	gold quality
stromal cell of endometrium	CL:0002255	71.11	gold quality
ganglionic eminence	UBERON:0004023	70.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.36	silver quality
tendon of biceps brachii	UBERON:0008188	69.11	gold quality
right coronary artery	UBERON:0001625	62.04	gold quality
buccal mucosa cell	CL:0002336	60.82	silver quality
tibia	UBERON:0000979	59.70	gold quality
left coronary artery	UBERON:0001626	56.52	gold quality
coronary artery	UBERON:0001621	56.06	gold quality
tibial artery	UBERON:0007610	55.74	gold quality
popliteal artery	UBERON:0002250	55.73	gold quality
colonic epithelium	UBERON:0000397	55.59	silver quality
lateral nuclear group of thalamus	UBERON:0002736	55.39	gold quality
hypothalamus	UBERON:0001898	53.78	gold quality
right atrium auricular region	UBERON:0006631	53.44	gold quality
tendon	UBERON:0000043	53.11	silver quality
cardiac atrium	UBERON:0002081	53.10	gold quality
ventral tegmental area	UBERON:0002691	51.88	silver quality
calcaneal tendon	UBERON:0003701	51.67	gold quality
ventricular zone	UBERON:0003053	50.33	gold quality
cerebellar vermis	UBERON:0004720	50.13	gold quality
amygdala	UBERON:0001876	49.70	gold quality
visceral pleura	UBERON:0002401	48.65	gold quality
cortical plate	UBERON:0005343	48.19	gold quality
liver	UBERON:0002107	47.50	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	904.21
E-MTAB-8894	yes	861.52
E-MTAB-9154	yes	840.65
E-GEOD-75140	yes	580.49
E-HCAD-5	no	920.54
E-ANND-3	no	6.03

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
GATA4
GNRHR
LMO3

JASPAR motifs

Motif	Name	Family
MA0701.1	LHX9	HD-LIM
MA0701.2	LHX9	HD-LIM
MA0701.3	LHX9	HD-LIM

JASPAR matrix evidence (PMIDs): PMID:18585360, PMID:18585359

Upstream regulators (CollecTRI, top): GATA4, ZFPM2

miRNA regulators (miRDB)

106 targeting LHX9, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 6)

• Lhx9 and Lhx1 serve as a binary switch in controlling the rostral versus caudal longitudinal turning of the caudal commissural axons. Lhx1 determines caudal turning and Lhx9 triggers rostral turning. (PMID:19545367)
• LHX9 gene is frequently silenced in pediatric malignant astrocytomas (PMID:19568415)
• that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly (PMID:29565736)
• LHX9, a p53-binding protein, inhibits the progression of glioma by suppressing glycolysis. (PMID:34536269)
• Increased LHX9 expression in alveolar epithelial type 2 cells of patients with chronic obstructive pulmonary disease. (PMID:34548271)
• Transcription factor LHX9 (LIM Homeobox 9) enhances pyruvate kinase PKM2 activity to induce glycolytic metabolic reprogramming in cancer stem cells, promoting gastric cancer progression. (PMID:37980488)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhx9	ENSDARG00000056979
mus_musculus	Lhx9	ENSMUSG00000019230
rattus_norvegicus	Lhx9	ENSRNOG00000010357

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), LHX4 (ENSG00000121454), LMO2 (ENSG00000135363), ZFHX2 (ENSG00000136367), LMX1B (ENSG00000136944), ZFHX3 (ENSG00000140836), LMO4 (ENSG00000143013), CRIP3 (ENSG00000146215), LHX8 (ENSG00000162624), LMX1A (ENSG00000162761), LMO1 (ENSG00000166407), CRIP2 (ENSG00000182809), CRIP1 (ENSG00000213145), LHX1 (ENSG00000273706)

Protein

Protein identifiers

LIM/homeobox protein Lhx9 — Q9NQ69 (reviewed: Q9NQ69)

All UniProt accessions (5): Q9NQ69, A0A087X083, A0A0C4DGY4, H0Y330, H0YL54

UniProt curated annotations — full annotation on UniProt →

Function. Involved in gonadal development.

Subunit / interactions. Interacts with LDB1 and LDB2.

Subcellular location. Nucleus.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NQ69-1	1	yes
Q9NQ69-2	2
Q9NQ69-3	3
Q9NQ69-4	4

RefSeq proteins (4): NP_001014434, NP_001357142, NP_001397856, NP_064589* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR001781	Znf_LIM	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (13 total): helix 3, region of interest 3, domain 2, splice variant 2, chain 1, DNA-binding region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2DMQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQ69-F1	66.92	0.28

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-1266738	Developmental Biology
R-HSA-376176	Signaling by ROBO receptors
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 133 (showing top): GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_NEUROGENESIS, AAAYRNCTG_UNKNOWN, USF_C, FOXD3_01, IRF7_01, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, FREAC3_01, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, GROSS_HYPOXIA_VIA_ELK3_DN, GROSS_HYPOXIA_VIA_HIF1A_DN, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP, GATA1_01, HFH4_01, GOBP_FEMALE_SEX_DIFFERENTIATION

GO Biological Process (9): regulation of transcription by RNA polymerase II (GO:0006357), cell population proliferation (GO:0008283), male gonad development (GO:0008584), female gonad development (GO:0008585), neuron differentiation (GO:0030182), gonad morphogenesis (GO:0035262), negative regulation of DNA-templated transcription (GO:0045892), dorsal spinal cord interneuron anterior axon guidance (GO:0097380), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (7): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), metal ion binding (GO:0046872), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

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

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ROBO receptors	1
Axon guidance	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gonad development	3
regulation of DNA-templated transcription	2
DNA-templated transcription	2
transcription by RNA polymerase II	1
cellular process	1
development of primary male sexual characteristics	1
development of primary female sexual characteristics	1
cell differentiation	1
generation of neurons	1
developmental process involved in reproduction	1
animal organ morphogenesis	1
negative regulation of RNA biosynthetic process	1
anterior/posterior axon guidance	1
dorsal spinal cord interneuron axon guidance	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	1
chromatin	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
cation binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1328 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHX9	NR5A1	Q13285	798
LHX9	POU4F1	Q01851	793
LHX9	NR0B1	P51843	747
LHX9	BARHL1	Q9BZE3	745
LHX9	WT1	P19544	743
LHX9	DENND1B	Q6P3S1	723
LHX9	NHLH1	Q02575	701
LHX9	ATOH1	Q92858	676
LHX9	AMH	P03971	674
LHX9	TBR1	Q16650	667
LHX9	NEK7	Q8TDX7	642
LHX9	SOX9	P48436	617
LHX9	SRY	Q05066	606
LHX9	LDB1	Q86U70	606
LHX9	VSX2	P58304	605

IntAct

24 interactions, top by confidence:

A	B	Type	Score
LHX9	CWF19L2	psi-mi:“MI:0915”(physical association)	0.560
LHX9	KHK	psi-mi:“MI:0915”(physical association)	0.560
CWF19L2	LHX9	psi-mi:“MI:0915”(physical association)	0.560
KHK	LHX9	psi-mi:“MI:0915”(physical association)	0.560
IGFN1	LHX9	psi-mi:“MI:0915”(physical association)	0.560
LDB1	LHX9	psi-mi:“MI:0915”(physical association)	0.560
UBTFL1	LHX9	psi-mi:“MI:0915”(physical association)	0.560
CSNK2A1	LHX9	psi-mi:“MI:0915”(physical association)	0.560
LHX9	LDB1	psi-mi:“MI:0914”(association)	0.350
IGFN1	LHX9	psi-mi:“MI:0915”(physical association)	0.000
LDB1	LHX9	psi-mi:“MI:0915”(physical association)	0.000
UBTFL1	LHX9	psi-mi:“MI:0915”(physical association)	0.000
CSNK2A1	LHX9	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): LHX9 (Two-hybrid), CWF19L2 (Two-hybrid), ZHX1 (Affinity Capture-MS), ANKRD17 (Affinity Capture-MS), SSBP3 (Affinity Capture-MS), SSBP4 (Affinity Capture-MS), LDB1 (Affinity Capture-MS), LHX9 (Two-hybrid), LDB1 (Affinity Capture-MS), SSBP3 (Affinity Capture-MS), PARP2 (Affinity Capture-MS), ZHX1 (Affinity Capture-MS), LHX9 (Two-hybrid), IGFN1 (Two-hybrid), LDB1 (Two-hybrid)

ESM2 similar proteins: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, G5EEA1, P20154, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53411, P53412, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q1LWV4, Q5IS44, Q5IS89, Q68EY3

Diamond homologs: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, O14639, O35652, O60663, O88609, O94929, O97581, P20154, P25791, P25800, P25801, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P50480, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53410, P53411, P53412, P53413, P53667, P53668

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

914 predictions. Top by Δscore:

Variant	Effect	Δscore
1:197919098:G:GT	donor_gain	1.0000
1:197921302:A:AG	acceptor_gain	1.0000
1:197921302:AGAAG:A	acceptor_gain	1.0000
1:197921303:G:GA	acceptor_gain	1.0000
1:197921303:GA:G	acceptor_gain	1.0000
1:197921303:GAA:G	acceptor_gain	1.0000
1:197921303:GAAGG:G	acceptor_gain	1.0000
1:197927791:CAGG:C	donor_loss	1.0000
1:197927792:AGGT:A	donor_loss	1.0000
1:197927793:GG:G	donor_loss	1.0000
1:197927794:GTA:G	donor_loss	1.0000
1:197927795:T:A	donor_loss	1.0000
1:197929222:G:GT	donor_gain	1.0000
1:197917538:GAGCA:G	donor_gain	0.9900
1:197918003:G:GT	donor_gain	0.9900
1:197919966:TTGCA:T	acceptor_loss	0.9900
1:197919968:GCA:G	acceptor_loss	0.9900
1:197919969:CAGG:C	acceptor_loss	0.9900
1:197919970:A:AG	acceptor_gain	0.9900
1:197919970:A:G	acceptor_loss	0.9900
1:197919970:AG:A	acceptor_gain	0.9900
1:197919970:AGG:A	acceptor_gain	0.9900
1:197919971:G:A	acceptor_loss	0.9900
1:197919971:G:GA	acceptor_gain	0.9900
1:197919971:GG:G	acceptor_gain	0.9900
1:197919971:GGG:G	acceptor_gain	0.9900
1:197919971:GGGC:G	acceptor_gain	0.9900
1:197919971:GGGCA:G	acceptor_gain	0.9900
1:197920140:G:GT	donor_gain	0.9900
1:197920145:T:TA	donor_gain	0.9900

AlphaMissense

2592 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:197920008:T:A	C71S	1.000
1:197920008:T:C	C71R	1.000
1:197920009:G:A	C71Y	1.000
1:197920009:G:C	C71S	1.000
1:197920009:G:T	C71F	1.000
1:197920010:C:G	C71W	1.000
1:197920015:G:A	G73D	1.000
1:197920017:T:A	C74S	1.000
1:197920017:T:C	C74R	1.000
1:197920018:G:A	C74Y	1.000
1:197920018:G:C	C74S	1.000
1:197920018:G:T	C74F	1.000
1:197920019:C:G	C74W	1.000
1:197920030:T:A	I78N	1.000
1:197920030:T:C	I78T	1.000
1:197920030:T:G	I78S	1.000
1:197920044:T:G	Y83D	1.000
1:197920048:T:C	L84P	1.000
1:197920051:T:C	L85P	1.000
1:197920054:C:A	A86D	1.000
1:197920068:T:A	W91R	1.000
1:197920068:T:C	W91R	1.000
1:197920069:G:C	W91S	1.000
1:197920070:G:C	W91C	1.000
1:197920070:G:T	W91C	1.000
1:197920071:C:A	H92N	1.000
1:197920071:C:G	H92D	1.000
1:197920072:A:G	H92R	1.000
1:197920072:A:T	H92L	1.000
1:197920073:T:A	H92Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000093342 (1:197934122 A>G), RS1000188878 (1:197916527 C>A,T), RS1000355963 (1:197911458 G>A,T), RS1000640398 (1:197929495 T>A), RS1000709761 (1:197922742 T>A), RS1000926108 (1:197915149 C>T), RS1001041689 (1:197921036 AT>A,ATT), RS1001068051 (1:197914858 G>A,T), RS1001079722 (1:197923104 G>A,C), RS1001501437 (1:197927257 T>A), RS1001605809 (1:197916148 T>C,G), RS1001644779 (1:197911017 G>C), RS1001668144 (1:197916458 C>A,G,T), RS1001764104 (1:197927593 T>A), RS1001799182 (1:197910848 A>C,G)

Disease associations

OMIM: gene MIM:606066 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (1): Pituitary stalk interruption syndrome (Orphanet:95496)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_965	Heel bone mineral density	9.000000e-12
GCST007325_101	General risk tolerance (MTAG)	2.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	increases methylation, decreases methylation	2
arsenite	increases methylation	1
butyraldehyde	increases expression	1
vanadyl sulfate	decreases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
Vorinostat	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Phthalic Acids	increases methylation	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thimerosal	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases expression	1
Vanadates	decreases expression	1
1-Methyl-4-phenylpyridinium	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3W8	SEES3-1V human LHX9, clone1	Embryonic stem cell	Male
CVCL_A3W9	SEES3-1V human LHX9, clone2	Embryonic stem cell	Male
CVCL_A3X0	SEES3-1V human LHX9, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)