LHX4

Summary

LHX4 (LIM homeobox 4, HGNC:21734) is a protein-coding gene on chromosome 1q25.2, encoding LIM/homeobox protein Lhx4 (Q969G2). May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung.

This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4.

Source: NCBI Gene 89884 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short stature-pituitary and cerebellar defects-small sella turcica syndrome (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 97 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 93
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_033343

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21734
Approved symbol	LHX4
Name	LIM homeobox 4
Location	1q25.2
Locus type	gene with protein product
Status	Approved
Aliases	Gsh4
Ensembl gene	ENSG00000121454
Ensembl biotype	protein_coding
OMIM	602146
Entrez	89884

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000263726, ENST00000558139, ENST00000561113, ENST00000930099

RefSeq mRNA: 1 — MANE Select: NM_033343 NM_033343

CCDS: CCDS1338

Canonical transcript exons

ENST00000263726 — 6 exons

Exon	Start	End
ENSE00000790177	180271835	180272006
ENSE00000822684	180248285	180248456
ENSE00000922041	180274185	180278984
ENSE00002557368	180230264	180230605
ENSE00003483063	180271380	180271534
ENSE00003630516	180266392	180266594

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 83.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6345 / max 47.3770, expressed in 130 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
6957	0.5927	128
6958	0.0419	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	83.74	silver quality
sperm	CL:0000019	76.68	silver quality
pancreatic ductal cell	CL:0002079	75.87	silver quality
secondary oocyte	CL:0000655	74.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.55	silver quality
tendon of biceps brachii	UBERON:0008188	70.39	gold quality
ileal mucosa	UBERON:0000331	68.06	silver quality
tibialis anterior	UBERON:0001385	67.43	silver quality
cerebellar vermis	UBERON:0004720	66.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.16	gold quality
cortical plate	UBERON:0005343	65.13	gold quality
cerebellar cortex	UBERON:0002129	64.70	gold quality
cerebellar hemisphere	UBERON:0002245	64.68	gold quality
left testis	UBERON:0004533	64.48	gold quality
lower esophagus mucosa	UBERON:0035834	64.47	gold quality
nasal cavity epithelium	UBERON:0005384	64.44	gold quality
body of pancreas	UBERON:0001150	63.80	gold quality
rectum	UBERON:0001052	63.60	gold quality
myocardium	UBERON:0002349	63.41	gold quality
right testis	UBERON:0004534	63.13	gold quality
testis	UBERON:0000473	63.10	gold quality
stromal cell of endometrium	CL:0002255	63.04	gold quality
cerebellum	UBERON:0002037	63.00	gold quality
bone marrow cell	CL:0002092	62.88	gold quality
right ovary	UBERON:0002118	62.24	gold quality
granulocyte	CL:0000094	62.08	gold quality
adenohypophysis	UBERON:0002196	62.03	gold quality
ventricular zone	UBERON:0003053	62.02	gold quality
ganglionic eminence	UBERON:0004023	61.83	gold quality
right lobe of thyroid gland	UBERON:0001119	61.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.19

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
AFP
CGA	Activation
FOXL2
FSHB	Unknown
GH1	Unknown
IFT172
LHX4
POU1F1	Activation
PRL	Unknown
TSHB	Unknown

Upstream regulators (CollecTRI, top): LHX4, SP1

miRNA regulators (miRDB)

42 targeting LHX4, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3688-3P	99.97	72.02	2834
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-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-4635	98.74	67.63	1339

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• germline mutations; phenotype characterized by short stature and by pituitary, hindbrain, and skull abnormalities (PMID:11567216)
• “Heterozygous splice site mutations within LHX4 are associated with combined pituitary hormone deficiency and isolated growth hormone deficiency… small sella turcica…persistent craniopharyngeal canal…ectopic posterior pituitary… " P. 207 (PMID:14714741)
• LHX4 expression is transient, and, at 6 weeks of development, is stronger at the caudal than at the cervical level. (PMID:15567726)
• Findings are consistent with the existence of LHX4-driven pathway leading to expression of GH through transcriptional activation of POU1F1. They argue against dominant-negative effect of mutant LHX4 proteins over normal LHX4. (PMID:15998782)
• endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein (PMID:17667940)
• We conclude Sp1 directly regulates Lhx4 gene expression. (PMID:18053794)
• LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. (PMID:18073311)
• three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. (PMID:18445675)
• A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial Pituitary stalk interruption syndrome. (PMID:21270112)
• data indicate that LHX4 may act as a potential tumor suppressor in hepatocarcinogenesis, suggesting that targeting LHX4 to downregulate AFP might have therapeutic implications (PMID:21965270)
• Variably penetrant pituitary insufficiency, including this severe and atypical presentation, can be correlated with LHX4 insufficiency and highlights the role of LHX4 for pituitary development. (PMID:22232309)
• This study is the first to describe, a gradual loss of ACTH in a patient carrying an LHX4 mutation. (PMID:23029363)
• Data indicate that HESX1, LHX4 and SOX3 polymorphisms may be associated with pituitary stalk interruption syndrome (PSIS). (PMID:23199197)
• we found that LHX4 upregulated beta-catenin levels in human colorectal cancer cell lines (PMID:25034524)
• A novel homozygous mutation in LHX4 associated with a lethal phenotype, implying that recessive mutations in LHX4 may be incompatible with life. (PMID:25871839)
• The study identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. (PMID:25955177)
• LHX4 Mutation is associated with Pituitary Deficits. (PMID:27820671)
• Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes. (PMID:37948564)
• In mice, a similar protein plays a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. (PMID:7913017)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhx4	ENSDARG00000039458
mus_musculus	Lhx4	ENSMUSG00000026468
rattus_norvegicus	Lhx4	ENSRNOG00000003595

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), LMO2 (ENSG00000135363), ZFHX2 (ENSG00000136367), LMX1B (ENSG00000136944), ZFHX3 (ENSG00000140836), LMO4 (ENSG00000143013), LHX9 (ENSG00000143355), CRIP3 (ENSG00000146215), LHX8 (ENSG00000162624), LMX1A (ENSG00000162761), LMO1 (ENSG00000166407), CRIP2 (ENSG00000182809), CRIP1 (ENSG00000213145), LHX1 (ENSG00000273706)

Protein

Protein identifiers

LIM/homeobox protein Lhx4 — Q969G2 (reviewed: Q969G2)

All UniProt accessions (3): A0A0S2Z5S4, Q969G2, H0YKF4

UniProt curated annotations — full annotation on UniProt →

Function. May play a critical role in the development of respiratory control mechanisms and in the normal growth and maturation of the lung. Binds preferentially to methylated DNA.

Subcellular location. Nucleus.

Disease relevance. Pituitary hormone deficiency, combined, 4 (CPHD4) [MIM:262700] Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD4 is characterized by complete or partial deficiencies of growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle stimulating hormone and adrenocorticotropic hormone. Clinical features include short stature, cerebellar defects, and small sella turcica. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving LHX4 may be a cause of acute lymphoblastic leukemia. Translocation t(1;14)(q25;q32) with IGHG1.

RefSeq proteins (1): NP_203129* (*=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
IPR047956	LHX4_LIM1	Domain
IPR049594	Lhx3/4-like_LIM2	Domain
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (17 total): sequence variant 5, region of interest 4, helix 3, domain 2, chain 1, sequence conflict 1, DNA-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5HOD	X-RAY DIFFRACTION	2.68

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969G2-F1	68.49	0.35

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: 275 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MAZ_Q6, GOBP_NEUROGENESIS, AP2_Q3, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, GOBP_SPINAL_CORD_MOTOR_NEURON_DIFFERENTIATION, GOBP_VENTRAL_SPINAL_CORD_DEVELOPMENT, GOBP_MOTOR_NEURON_AXON_GUIDANCE, TCF4_Q5, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION, AFFAR_YY1_TARGETS_DN, LEF1_Q6, CAAGGAT_MIR362

GO Biological Process (10): placenta development (GO:0001890), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), motor neuron axon guidance (GO:0008045), animal organ morphogenesis (GO:0009887), medial motor column neuron differentiation (GO:0021526), neuron differentiation (GO:0030182), negative regulation of apoptotic process (GO:0043066), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), zinc ion binding (GO:0008270), methyl-CpG binding (GO:0008327), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

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
animal organ development	2
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
sequence-specific DNA binding	2
regulation of DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
axon guidance	1
anatomical structure morphogenesis	1
cell differentiation in spinal cord	1
somatic motor neuron differentiation	1
neuron differentiation	1
cell differentiation	1
generation of neurons	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
transcription cis-regulatory region binding	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
transition metal ion binding	1
nucleotide binding	1
DNA binding	1
double-stranded DNA binding	1
nucleic acid binding	1
binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1150 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHX4	POU1F1	P28069	891
LHX4	ESX1	Q8N693	823
LHX4	SYNM	O15061	771
LHX4	SOX3	P35714	724
LHX4	OTX2	P32243	698
LHX4	ISL2	Q96A47	683
LHX4	TSC22D2	O75157	670
LHX4	PROKR2	Q8NFJ6	656
LHX4	RAB2A	P08886	651
LHX4	TSC22D4	Q9Y3Q8	650
LHX4	POMC	P01189	627
LHX4	PITX1	P78337	624
LHX4	TSC22D1	Q15714	604
LHX4	GHRHR	Q02643	596
LHX4	TBX19	O60806	589

IntAct

193 interactions, top by confidence:

A	B	Type	Score
LHX4	ORC6	psi-mi:“MI:0915”(physical association)	0.780
ORC6	LHX4	psi-mi:“MI:0915”(physical association)	0.780
LHX4	ISL2	psi-mi:“MI:0915”(physical association)	0.760
ISL1	LHX4	psi-mi:“MI:0915”(physical association)	0.750
SH2D1A	LHX4	psi-mi:“MI:0915”(physical association)	0.740
LHX4	SH2D1A	psi-mi:“MI:0915”(physical association)	0.740
SNRNP25	LHX4	psi-mi:“MI:0915”(physical association)	0.720
LHX4	SNRNP25	psi-mi:“MI:0915”(physical association)	0.720
PYGO1	BCL9	psi-mi:“MI:0914”(association)	0.700
LHX4	USP2	psi-mi:“MI:0915”(physical association)	0.670
LHX4	CHCHD2	psi-mi:“MI:0915”(physical association)	0.670
USP2	LHX4	psi-mi:“MI:0915”(physical association)	0.670
CHCHD2	LHX4	psi-mi:“MI:0915”(physical association)	0.670
LDB1	LHX4	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (223): LHX4 (Two-hybrid), LHX4 (Two-hybrid), LHX4 (Two-hybrid), LHX4 (Two-hybrid), LHX4 (Two-hybrid), LHX4 (Two-hybrid), LHX4 (Two-hybrid), LONRF1 (Two-hybrid), FDX1L (Two-hybrid), LHX4 (Affinity Capture-MS), LHX4 (Affinity Capture-MS), CEP97 (Affinity Capture-MS), ZNF574 (Affinity Capture-MS), CHMP1A (Affinity Capture-MS), CYFIP2 (Affinity Capture-MS)

ESM2 similar proteins: A0JNI8, A2I8Z7, A2PZF9, G5EC36, G5EE86, G5EEA1, P09088, P20154, P20271, P29673, P29674, P34764, P34765, P36198, P36200, P37137, P48742, P50211, P50212, P50458, P52889, P53405, P53406, P53407, P53408, P53409, P53411, P53412, P53776, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q1LWV4, Q5IS44

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

2 interactions.

A	Effect	B	Mechanism
LHX4	“up-regulates quantity by expression”	POU1F1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	51
Likely benign	16
Benign	14

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1428279	NM_033343.4(LHX4):c.382del (p.Asp128fs)	Pathogenic
18444	NM_033343.4(LHX4):c.293dup (p.Thr99fs)	Pathogenic
280160	NM_033343.4(LHX4):c.295del (p.Thr99fs)	Pathogenic
1098404	NM_033343.4(LHX4):c.171T>G (p.Cys57Trp)	Likely pathogenic
2031127	NM_033343.4(LHX4):c.77-2A>G	Likely pathogenic

SpliceAI

1828 predictions. Top by Δscore:

Variant	Effect	Δscore
1:180230601:GCAAC:G	donor_gain	1.0000
1:180230606:G:GG	donor_gain	1.0000
1:180248280:CACA:C	acceptor_loss	1.0000
1:180248282:C:G	acceptor_gain	1.0000
1:180248283:A:AC	acceptor_loss	1.0000
1:180248283:A:AG	acceptor_gain	1.0000
1:180248284:G:GT	acceptor_gain	1.0000
1:180248284:GA:G	acceptor_gain	1.0000
1:180248284:GAGA:G	acceptor_gain	1.0000
1:180248284:GAGAT:G	acceptor_gain	1.0000
1:180248454:CAA:C	donor_gain	1.0000
1:180248455:AA:A	donor_gain	1.0000
1:180248456:AGT:A	donor_loss	1.0000
1:180248457:G:GG	donor_gain	1.0000
1:180248457:G:T	donor_loss	1.0000
1:180248458:T:G	donor_loss	1.0000
1:180266590:GAACG:G	donor_gain	1.0000
1:180266591:AACG:A	donor_gain	1.0000
1:180266593:CG:C	donor_gain	1.0000
1:180266593:CGGTA:C	donor_loss	1.0000
1:180266594:GG:G	donor_gain	1.0000
1:180266594:GGTAA:G	donor_loss	1.0000
1:180266595:G:GG	donor_gain	1.0000
1:180266595:GTA:G	donor_loss	1.0000
1:180266596:T:G	donor_loss	1.0000
1:180271377:CA:C	acceptor_loss	1.0000
1:180271378:A:AG	acceptor_gain	1.0000
1:180271378:AGAT:A	acceptor_gain	1.0000
1:180271379:G:GC	acceptor_gain	1.0000
1:180271379:GA:G	acceptor_gain	1.0000

AlphaMissense

2591 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:180248296:T:A	C30S	1.000
1:180248296:T:C	C30R	1.000
1:180248297:G:A	C30Y	1.000
1:180248297:G:C	C30S	1.000
1:180248298:C:G	C30W	1.000
1:180248305:T:A	C33S	1.000
1:180248305:T:C	C33R	1.000
1:180248306:G:A	C33Y	1.000
1:180248306:G:C	C33S	1.000
1:180248306:G:T	C33F	1.000
1:180248307:C:G	C33W	1.000
1:180248318:T:A	I37N	1.000
1:180248318:T:C	I37T	1.000
1:180248318:T:G	I37S	1.000
1:180248329:T:C	F41L	1.000
1:180248331:C:A	F41L	1.000
1:180248331:C:G	F41L	1.000
1:180248336:T:C	L43P	1.000
1:180248356:T:A	W50R	1.000
1:180248356:T:C	W50R	1.000
1:180248358:G:C	W50C	1.000
1:180248358:G:T	W50C	1.000
1:180248359:C:A	H51N	1.000
1:180248359:C:G	H51D	1.000
1:180248360:A:T	H51L	1.000
1:180248361:C:A	H51Q	1.000
1:180248361:C:G	H51Q	1.000
1:180248368:T:A	C54S	1.000
1:180248368:T:C	C54R	1.000
1:180248369:G:A	C54Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000050343 (1:180243084 G>A), RS1000059069 (1:180231581 A>C,G), RS1000080884 (1:180255295 C>T), RS1000118209 (1:180237944 C>T), RS1000133127 (1:180255379 TACAC>T,TAC), RS1000163051 (1:180270915 G>A), RS1000203220 (1:180269403 G>A), RS1000226549 (1:180264083 G>A), RS1000254261 (1:180269657 T>A,G), RS1000322397 (1:180264985 G>A), RS1000329246 (1:180258323 G>A), RS1000448230 (1:180227442 C>G,T), RS1000476166 (1:180250459 C>T), RS1000516442 (1:180227881 G>A), RS1000566986 (1:180238908 A>G,T)

Disease associations

OMIM: gene MIM:602146 | disease phenotypes: MIM:262700, MIM:613038

GenCC curated gene-disease

Disease	Classification	Inheritance
short stature-pituitary and cerebellar defects-small sella turcica syndrome	Definitive	Autosomal dominant
hypothyroidism due to deficient transcription factors involved in pituitary development or function	Supportive	Autosomal dominant
combined pituitary hormone deficiencies, genetic form	Supportive	Autosomal dominant
pituitary stalk interruption syndrome	Supportive	Autosomal dominant

Mondo (5): short stature-pituitary and cerebellar defects-small sella turcica syndrome (MONDO:0009880), pituitary hormone deficiency, combined, 1 (MONDO:0024464), hypothyroidism due to deficient transcription factors involved in pituitary development or function (MONDO:0016411), combined pituitary hormone deficiencies, genetic form (MONDO:0013099), pituitary stalk interruption syndrome (MONDO:0019828)

Orphanet (1): Short stature-pituitary and cerebellar defects-small sella turcica syndrome (Orphanet:85442)

HPO phenotypes

93 total (30 of 93 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000141	Amenorrhea
HP:0000158	Macroglossia
HP:0000270	Delayed cranial suture closure
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000470	Short neck
HP:0000478	Abnormality of the eye
HP:0000609	Optic nerve hypoplasia
HP:0000786	Primary amenorrhea
HP:0000789	Infertility
HP:0000821	Hypothyroidism
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000835	Adrenal hypoplasia
HP:0000839	Pituitary dwarfism
HP:0000846	Adrenal insufficiency
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000871	Panhypopituitarism
HP:0000873	Diabetes insipidus
HP:0000938	Osteopenia
HP:0001161	Hand polydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_371	Refractive error	3.000000e-09

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567803	Pituitary Hormone Deficiency, Combined, 1 (supp.)
C567492	Pituitary Hormone Deficiency, Combined, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases methylation, increases expression	2
bisphenol F	affects cotreatment, increases methylation	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
arsenite	increases methylation	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
mercuric bromide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
abrine	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects binding, increases reaction, increases expression	1
Ethinyl Estradiol	increases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Methapyrilene	increases methylation	1
Silicon Dioxide	increases expression	1
Smoke	increases expression, affects binding, increases reaction	1
Testosterone	affects cotreatment, increases expression, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	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_A3V6	SEES3-1V human LHX4, clone1	Embryonic stem cell	Male
CVCL_A3V7	SEES3-1V human LHX4, clone2	Embryonic stem cell	Male
CVCL_A3V8	SEES3-1V human LHX4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

3 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)
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns