LHX3

Summary

LHX3 (LIM homeobox 3, HGNC:6595) is a protein-coding gene on chromosome 9q34.3, encoding LIM/homeobox protein Lhx3 (Q9UBR4). Transcription factor.

This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 8022 — RefSeq curated summary.

At a glance

• Gene–disease (curated): non-acquired combined pituitary hormone deficiency with spine abnormalities (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 21
• Clinical variants (ClinVar): 648 total — 24 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 59
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_178138

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6595
Approved symbol	LHX3
Name	LIM homeobox 3
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000107187
Ensembl biotype	protein_coding
OMIM	600577
Entrez	8022

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000371746, ENST00000371748, ENST00000619587, ENST00000645419

RefSeq mRNA: 3 — MANE Select: NM_178138 NM_001363746, NM_014564, NM_178138

CCDS: CCDS6994, CCDS6995, CCDS87713

Canonical transcript exons

ENST00000371748 — 6 exons

Exon	Start	End
ENSE00000733852	136199678	136199880
ENSE00000828302	136198908	136199059
ENSE00000828303	136198652	136198820
ENSE00001197504	136204934	136205128
ENSE00001323733	136200582	136200753
ENSE00001456011	136196250	136197743

Expression profiles

Bgee: expression breadth broad, 22 present calls, max score 90.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4358 / max 171.8256, expressed in 20 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103132	0.2345	13
103137	0.0983	12
103134	0.0521	10
103133	0.0508	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	90.76	gold quality
diaphragm	UBERON:0001103	88.71	gold quality
adenohypophysis	UBERON:0002196	88.21	gold quality
type B pancreatic cell	CL:0000169	86.93	gold quality
olfactory bulb	UBERON:0002264	86.82	gold quality
hair follicle	UBERON:0002073	79.81	gold quality
cervix squamous epithelium	UBERON:0006922	78.69	gold quality
mucosa of urinary bladder	UBERON:0001259	75.84	gold quality
pancreatic ductal cell	CL:0002079	75.66	silver quality
tongue squamous epithelium	UBERON:0006919	75.11	gold quality
tibialis anterior	UBERON:0001385	74.66	silver quality
triceps brachii	UBERON:0001509	74.13	gold quality
gluteal muscle	UBERON:0002000	74.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.33	gold quality
cervix epithelium	UBERON:0004801	71.21	gold quality
upper arm skin	UBERON:0004263	69.09	gold quality
cardiac muscle of right atrium	UBERON:0003379	68.82	gold quality
left ventricle myocardium	UBERON:0006566	68.81	gold quality
CA1 field of hippocampus	UBERON:0003881	68.75	gold quality
quadriceps femoris	UBERON:0001377	67.12	gold quality
ileal mucosa	UBERON:0000331	66.85	silver quality
decidua	UBERON:0002450	66.30	gold quality
nasal cavity epithelium	UBERON:0005384	66.29	gold quality
choroid plexus epithelium	UBERON:0003911	66.20	silver quality
vastus lateralis	UBERON:0001379	65.73	gold quality
Brodmann (1909) area 46	UBERON:0006483	64.23	gold quality
deltoid	UBERON:0001476	63.36	silver quality
endothelial cell	CL:0000115	62.74	gold quality
mucosa of paranasal sinus	UBERON:0005030	62.64	gold quality
orbitofrontal cortex	UBERON:0004167	62.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.31

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
ADAM2
ANP32A
CGA	Activation
ESR1
FOXL2
FSHB	Activation
GLB1
GNRHR	Unknown
HESX1	Activation
INHBA
LHB
LHX3
PITX1
PRL	Unknown
TPM1
TSHB	Unknown
VSX2	Activation

Upstream regulators (CollecTRI, top): FOXP1, LHX3, POU4F3, RBPJ, SOX2, SP1

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 27)

• The Lhx3 gene encodes two isoforms, LHX3a and LHX3b, that differ in their amino-terminal sequences. A novel LHX3 protein (M2-LHX3) is identified and it is determined that this molecule is generated by an internal translation initiation codon. (PMID:11470784)
• “Mutations in LHX3 are associated with a short neck combination with GHD (growth hormone deficiecy), PRL(prolactin) and TSH (thyroid stimulating hormone) and gonadotropin deficiency” p. 278 (PMID:14646405)
• “Mutations within LHX3 are associated with recessive combined pituitary hormone deficiency, with sparing of cortisol secretion…” P. 207 (PMID:14714741)
• LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell. (PMID:15271874)
• identified unique amino acids within LHX3 that are important for its transcriptional activity and are phosphorylated (PMID:15517599)
• LHX3 is expressed at all stages of early development. (PMID:15567726)
• Specificity protein 1 is a regulator of both promoters through interaction with GC boxes and also, a distal element within intron 1a that is recognized by nuclear factor I is critical for hLHX3b promoter function. (PMID:16179410)
• The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation. (PMID:16394081)
• Lhx3expression of Isl-1 and Lhx3, together with steroidogenic factor 1 (SF-1), culminates in the activation of both the rat as well as human GnRH-R promoter, suggesting that this combination is evolutionarily conserved among mammals (PMID:16613990)
• in 7 combined pituitary hormone deficiency patients from 4 consanguineous pedigrees, 4 novel, recessive mutations were identified: a deletion of the entire gene, mutations causing truncated proteins & a mutation causing a substitution in the homeodomain (PMID:17327381)
• LHX3 mutations is associated with sensorineural hearing loss and interaction between LHX3 and SOX2 may contribute to the development of the inner ear and the anterior pituitary. (PMID:18407919)
• Although the LIM interaction domain of Ldb1 (Ldb1(LID)) and Isl1(LBD) share low levels of sequence homology, X-ray and NMR structures reveal that they bind Lhx3 in an identical manner, that is, Isl1(LBD) mimics Ldb1(LID). (PMID:18583962)
• Existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis in LIM3 mutated patients. (PMID:19126629)
• A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci. (PMID:20189936)
• LHX3 mutations are a rare cause of hypopituitarism. We report on a patient with a novel LHX3 mutation in exon 2 with the phenotype of combined pituitary hormone deficiency with short neck and sensorineural hearing impairment. [review] (PMID:21249393)
• This study establishes ISL1 as a novel transcriptional regulator of LHX3 and describes a potential mechanism for regulation by PITX1. (PMID:22194342)
• This study of the first nonconsanguineous patient with LHX3 mutations demonstrates the pleiotropic roles of LHX3 during development and its full involvement in the complex disease phenotype of syndromic combined pituitary hormone deficiency. (PMID:22238406)
• descriprion of pediatric patients with combined pituitary hormone deficiency with a novel mutation in LHX3; the T194R mutation affects a critical residue in the LHX3 protein; study extends understanding of phenotypic features, molecular mechanism and developmental course associated with mutations in the LHX3 gene (PMID:22286346)
• The present study was unable to confirm a significant association of all of the three SNPs, rs12338076 in LHX3-QSOX2, and rs1457595 and rs17032362 in IGF1, with adult height in our study population. (PMID:22503243)
• Data suggest that low serum FSH (follicle stimulating hormone) levels in men with SNP in promoter region of FSHB (FSH beta subunit; -211G/T) result from reduced LHX3 binding to FSHB promoter and down-regulation of FSHB transcription in gonadotrophs. (PMID:23766128)
• The downstream enhancer region of LHX3 in regulating gene expression at the cellular level during development, is reported. (PMID:24100213)
• LHX3 is upregulated in high-grade oligodendroglioma. (PMID:25399296)
• investigated the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey (PMID:25500790)
• Further functional studies show that forced expression of LHX3 in lung cancer cells obviously promotes cell proliferation and invasion, whereas inhibits cell apoptosis. In summary, LHX3 is an early-stage and radiosensitivity prognostic biomarker, and a novel potential oncogene in lung adenocarcinoma . (PMID:28731174)
• Study did not identify HESX1 and LHX3 mutations by Sanger in brazilian patients with combined pituitary hormone deficiency (PMID:28734020)
• LHX3 expression is significantly increased in carcinoma tissues, and associated with clinical stage and metastasis of patients. LHX3 expression is much higher in the advanced-stage patients than the early-stage patients, and is sharply increased in metastasic patients. (PMID:31306102)
• Generation and optimization of highly pure motor neurons from human induced pluripotent stem cells via lentiviral delivery of transcription factors. (PMID:32783653)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	LHX3	ENSDARG00000003803
mus_musculus	Lhx3	ENSMUSG00000026934
rattus_norvegicus	Lhx3	ENSRNOG00000018427

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), LHX5 (ENSG00000089116), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX4 (ENSG00000121454), 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 Lhx3 — Q9UBR4 (reviewed: Q9UBR4)

All UniProt accessions (4): Q9UBR4, F1T0D5, F1T0D7, F1T0D9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor. Recognizes and binds to the consensus sequence motif 5’-AATTAATTA-3’ in the regulatory elements of target genes, such as glycoprotein hormones alpha chain CGA and visual system homeobox CHX10, positively modulating transcription; transcription can be co-activated by LDB2. Synergistically enhances transcription from the prolactin promoter in cooperation with POU1F1/Pit-1. Required for the establishment of the specialized cells of the pituitary gland and the nervous system. Involved in the development of interneurons and motor neurons in cooperation with LDB1 and ISL1.

Subunit / interactions. Interacts with POU1F1. At neuronal promoters, interacts with LDB1, in motor neurons LDB1 is displaced by ISL1 and a ternary complex is formed in which ISL1 contacts both LHX3 and LDB1; allosteric structural changes in the DNA binding domain of LHX3, induced by the ISL1-LHX3 interaction, may explain differences in sequence specificity of the different complexes. Interacts with LDB2. May interact with CITED2/MRG1.

Subcellular location. Nucleus.

Disease relevance. Pituitary hormone deficiency, combined, 3 (CPHD3) [MIM:221750] Combined pituitary hormone deficiency is defined as the impaired production of growth hormone and one or more of the other five anterior pituitary hormones. CPHD3 is characterized by a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The LIM domain specifically interacts with the Pit-1 POU domain and is required for synergistic interactions with Pit-1, but not for basal transcriptional activation events.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBR4-1	A	yes
Q9UBR4-2	B

RefSeq proteins (3): NP_001350675, NP_055379, NP_835258* (*=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
IPR049593	Lhx3_LIM1	Domain
IPR049594	Lhx3/4-like_LIM2	Domain
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (17 total): modified residue 5, sequence variant 4, domain 2, chain 1, splice variant 1, sequence conflict 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBR4-F1	68.68	0.33

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 (5): 238, 63, 71, 227, 234

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: 274 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GCANCTGNY_MYOD_Q6, DARWICHE_SKIN_TUMOR_PROMOTER_UP, GOBP_PITUITARY_GLAND_DEVELOPMENT, DARWICHE_PAPILLOMA_RISK_LOW_UP, GOBP_NEUROGENESIS, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, CAGCTG_AP4_Q5, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_SPINAL_CORD_MOTOR_NEURON_DIFFERENTIATION, GOBP_VENTRAL_SPINAL_CORD_DEVELOPMENT

GO Biological Process (21): 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), spinal cord motor neuron cell fate specification (GO:0021520), ventral spinal cord interneuron specification (GO:0021521), medial motor column neuron differentiation (GO:0021526), spinal cord association neuron differentiation (GO:0021527), neuron differentiation (GO:0030182), lung development (GO:0030324), negative regulation of apoptotic process (GO:0043066), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), inner ear development (GO:0048839), somatotropin secreting cell differentiation (GO:0060126), prolactin secreting cell differentiation (GO:0060127), thyroid-stimulating hormone-secreting cell differentiation (GO:0060129), regulation of DNA-templated transcription (GO:0006355), dorsal/ventral pattern formation (GO:0009953), pituitary gland development (GO:0021983)

GO Molecular Function (13): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), zinc ion binding (GO:0008270), sequence-specific DNA binding (GO:0043565), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), transcription cis-regulatory region binding (GO:0000976), transcription coregulator binding (GO:0001221), DNA binding (GO:0003677), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), transcription regulator complex (GO:0005667)

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	3
cell differentiation	3
adenohypophysis development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
neuron fate specification	2
cell differentiation in spinal cord	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
axon guidance	1
anatomical structure morphogenesis	1
spinal cord motor neuron differentiation	1
cell fate specification involved in pattern specification	1
ventral spinal cord interneuron fate commitment	1
somatic motor neuron differentiation	1
neuron differentiation	1
dorsal spinal cord development	1
central nervous system neuron differentiation	1
generation of neurons	1
respiratory tube development	1
respiratory system development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
ear development	1
anatomical structure development	1
glandular epithelial cell differentiation	1
forebrain neuron differentiation	1
neuroendocrine cell differentiation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regionalization	1
transcription cis-regulatory region binding	1
cis-regulatory region sequence-specific DNA binding	1

Protein interactions and networks

STRING

1456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHX3	LDB1	Q86U70	995
LHX3	ISL1	P20663	985
LHX3	LDB2	O43679	907
LHX3	NEUROG2	Q9H2A3	889
LHX3	POU1F1	P28069	864
LHX3	ESX1	Q8N693	774
LHX3	LIM2	P55344	765
LHX3	SYNM	O15061	750
LHX3	OLIG2	Q13516	725
LHX3	ISL2	Q96A47	704
LHX3	RLIM	Q9NVW2	702
LHX3	TSHB	P01222	700
LHX3	PITX2	Q99697	694
LHX3	RAB2A	P08886	685
LHX3	NEUROD4	Q9HD90	679

IntAct

9 interactions, top by confidence:

A	B	Type	Score
LHX3	LDB1	psi-mi:“MI:0914”(association)	0.570
NFIA	LHX3	psi-mi:“MI:0915”(physical association)	0.470
LHX4	LHX3	psi-mi:“MI:0915”(physical association)	0.400
NFIB	LHX3	psi-mi:“MI:0915”(physical association)	0.400
NFIC	LHX3	psi-mi:“MI:0915”(physical association)	0.400
LHX3	HAL	psi-mi:“MI:0914”(association)	0.350
LHX3	TSPY2	psi-mi:“MI:0914”(association)	0.350
LHX3	BCL9	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (196): LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), LHX3 (Two-hybrid), CCDC6 (Two-hybrid), PARP11 (Two-hybrid)

ESM2 similar proteins: A5PMU4, O60663, O75541, O88609, O97581, P29674, P36200, P48742, P50211, P50212, P50480, P50481, P52889, P53405, P53406, P53407, P53408, P53409, P53410, P53411, P53412, P53413, P53776, P61371, P61372, P61373, P61374, P61375, P61376, P63006, P63007, P63008, Q04650, Q32KS7, Q5IS44, Q5IS89, Q60564, Q6H8Q1, Q6KC51, Q6PD05

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

7 interactions.

A	Effect	B	Mechanism
LHX3	“up-regulates activity”	ISL1	binding
LHX3	“up-regulates activity”	ISL2	binding
LHX3	“up-regulates quantity by expression”	FSHB	“transcriptional regulation”
CREBBP	“up-regulates activity”	LHX3	binding
LHX3	“up-regulates quantity by expression”	CGA	“transcriptional regulation”
ROCK2	“up-regulates activity”	LHX3	phosphorylation
POU4F3	“up-regulates quantity by expression”	LHX3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	26
Uncertain significance	212
Likely benign	333
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070291	NM_178138.6(LHX3):c.80-2A>G	Pathogenic
1073213	NM_178138.6(LHX3):c.214C>T (p.Arg72Ter)	Pathogenic
1073694	NM_178138.6(LHX3):c.576del (p.Glu193fs)	Pathogenic
1350624	NM_178138.6(LHX3):c.502C>T (p.Gln168Ter)	Pathogenic
2110904	NM_178138.6(LHX3):c.79+1920del	Pathogenic
2425955	NC_000009.11:g.(?139089161)(139096868_?)del	Pathogenic
2444147	NM_178138.6(LHX3):c.354C>A (p.Cys118Ter)	Pathogenic
2705534	NM_178138.6(LHX3):c.79+1973del	Pathogenic
2714452	NM_178138.6(LHX3):c.79+1956_79+1957insT	Pathogenic
2790005	NM_178138.6(LHX3):c.165T>A (p.Cys55Ter)	Pathogenic
2851429	NM_178138.6(LHX3):c.233del (p.Cys78fs)	Pathogenic
3245346	NC_000009.11:g.(?139094782)(139096868_?)del	Pathogenic
3630033	NM_178138.6(LHX3):c.528C>G (p.Tyr176Ter)	Pathogenic
4069850	NM_178138.6(LHX3):c.451C>T (p.Arg151Ter)	Pathogenic
4279483	GRCh37/hg19 9q34.3(chr9:139020257-139135215)x1	Pathogenic
9021	NM_178138.6(LHX3):c.332A>G (p.Tyr111Cys)	Pathogenic
9022	NM_178138.6(LHX3):c.452_454+20del	Pathogenic
9023	NM_178138.6(LHX3):c.96del (p.Gly33fs)	Pathogenic
9025	NM_178138.6(LHX3):c.287_288delinsTCCT (p.Gly96fs)	Pathogenic
9026	NC_000009.12:g.(?136197325)(136205012_?)del	Pathogenic
9027	NM_178138.6(LHX3):c.672G>A (p.Trp224Ter)	Pathogenic
9028	NM_178138.6(LHX3):c.80-530_776-454del	Pathogenic
9029	NM_178138.6(LHX3):c.133A>T (p.Lys45Ter)	Pathogenic
936489	NM_178138.6(LHX3):c.79+1939_79+1940insAT	Pathogenic
1067231	NM_178138.6(LHX3):c.607-3_630del	Likely pathogenic
1324663	NM_178138.6(LHX3):c.280C>T (p.Gln94Ter)	Likely pathogenic
1341562	NM_178138.6(LHX3):c.581C>G (p.Thr194Arg)	Likely pathogenic
1494222	NM_178138.6(LHX3):c.79+1990T>G	Likely pathogenic
2043249	NM_178138.6(LHX3):c.428_454+69del	Likely pathogenic
2059825	NM_178138.6(LHX3):c.606+1G>A	Likely pathogenic

SpliceAI

1225 predictions. Top by Δscore:

Variant	Effect	Δscore
9:136197739:CTCAT:C	acceptor_gain	1.0000
9:136197741:CAT:C	acceptor_gain	1.0000
9:136197743:TC:T	acceptor_loss	1.0000
9:136197744:C:CC	acceptor_gain	1.0000
9:136197744:CTG:C	acceptor_loss	1.0000
9:136197745:T:A	acceptor_loss	1.0000
9:136198646:GCCTA:G	donor_loss	1.0000
9:136198648:CTA:C	donor_loss	1.0000
9:136198650:A:AC	donor_gain	1.0000
9:136198651:C:CC	donor_gain	1.0000
9:136198651:C:CT	donor_loss	1.0000
9:136198687:T:TA	donor_gain	1.0000
9:136198816:CAAAC:C	acceptor_gain	1.0000
9:136198817:AAAC:A	acceptor_gain	1.0000
9:136198818:AAC:A	acceptor_gain	1.0000
9:136198903:CTGA:C	donor_loss	1.0000
9:136198904:TGAC:T	donor_loss	1.0000
9:136198905:GAC:G	donor_loss	1.0000
9:136198906:A:C	donor_loss	1.0000
9:136198907:C:CT	donor_loss	1.0000
9:136199060:C:CC	acceptor_gain	1.0000
9:136199673:CTGA:C	donor_loss	1.0000
9:136199674:TGA:T	donor_loss	1.0000
9:136199675:GAC:G	donor_loss	1.0000
9:136199677:CCTCG:C	donor_gain	1.0000
9:136199878:CGC:C	acceptor_gain	1.0000
9:136200576:GCTCA:G	donor_loss	1.0000
9:136200577:CTCA:C	donor_loss	1.0000
9:136200578:TCA:T	donor_loss	1.0000
9:136200580:A:AC	donor_gain	1.0000

AlphaMissense

2572 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:136198783:A:G	L215P	1.000
9:136198785:C:A	R214S	1.000
9:136198785:C:G	R214S	1.000
9:136198786:C:A	R214M	1.000
9:136198786:C:G	R214T	1.000
9:136198790:T:C	K213E	1.000
9:136198794:C:A	K211N	1.000
9:136198794:C:G	K211N	1.000
9:136198795:T:A	K211M	1.000
9:136198796:T:C	K211E	1.000
9:136198796:T:G	K211Q	1.000
9:136198798:G:A	A210V	1.000
9:136198798:G:T	A210D	1.000
9:136198799:C:G	A210P	1.000
9:136198801:C:G	R209P	1.000
9:136198801:C:T	R209Q	1.000
9:136198802:G:A	R209W	1.000
9:136198802:G:C	R209G	1.000
9:136198804:C:G	R208P	1.000
9:136198805:G:T	R208S	1.000
9:136198806:G:C	N207K	1.000
9:136198806:G:T	N207K	1.000
9:136198807:T:A	N207I	1.000
9:136198807:T:C	N207S	1.000
9:136198807:T:G	N207T	1.000
9:136198808:T:A	N207Y	1.000
9:136198808:T:C	N207D	1.000
9:136198808:T:G	N207H	1.000
9:136198809:C:A	Q206H	1.000
9:136198809:C:G	Q206H	1.000

dbSNP variants (sampled 300 via entrez): RS1000002321 (9:136202846 G>A,T), RS1000004516 (9:136196331 G>A), RS1000049571 (9:136198685 C>T), RS1000057804 (9:136202969 G>T), RS1000080219 (9:136198470 T>C), RS1000276016 (9:136197989 G>A,C), RS1000351489 (9:136201626 A>C), RS1000881692 (9:136196828 C>T), RS1001005191 (9:136201958 C>A,T), RS1001059068 (9:136202153 C>T), RS1001405592 (9:136202803 G>A), RS1001563096 (9:136196644 T>G), RS1001645542 (9:136198167 G>A), RS1001777297 (9:136198516 T>C,G), RS1001886957 (9:136202618 C>G)

Disease associations

OMIM: gene MIM:600577 | disease phenotypes: MIM:221750, MIM:613038

GenCC curated gene-disease

Disease	Classification	Inheritance
non-acquired combined pituitary hormone deficiency with spine abnormalities	Definitive	Autosomal recessive
hypothyroidism due to deficient transcription factors involved in pituitary development or function	Supportive	Autosomal dominant

Mondo (6): non-acquired combined pituitary hormone deficiency with spine abnormalities (MONDO:0009091), combined pituitary hormone deficiencies, genetic form (MONDO:0013099), amenorrhea (MONDO:0001836), pituitary hormone deficiency, combined, 1 (MONDO:0024464), congenital hypothyroidism (MONDO:0018612), hypothyroidism due to deficient transcription factors involved in pituitary development or function (MONDO:0016411)

Orphanet (3): Non-acquired combined pituitary hormone deficiency-sensorineural hearing loss-spine abnormalities syndrome (Orphanet:231720), Combined pituitary hormone deficiencies, genetic forms (Orphanet:95494), Congenital hypothyroidism (Orphanet:442)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000158	Macroglossia
HP:0000270	Delayed cranial suture closure
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000470	Short neck
HP:0000609	Optic nerve hypoplasia
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000830	Anterior hypopituitarism
HP:0000839	Pituitary dwarfism
HP:0000871	Panhypopituitarism
HP:0001161	Hand polydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001265	Hyporeflexia
HP:0001274	Agenesis of corpus callosum
HP:0001317	Abnormal cerebellum morphology
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001662	Bradycardia
HP:0001943	Hypoglycemia
HP:0001999	Abnormal facial shape
HP:0002019	Constipation
HP:0002045	Hypothermia
HP:0002920	Decreased circulating ACTH concentration
HP:0003423	Thoracolumbar kyphoscoliosis
HP:0004322	Short stature
HP:0004491	Large posterior fontanelle

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000611_15	Height	2.000000e-08
GCST001856_42	Thyroid hormone levels	5.000000e-08
GCST001856_43	Thyroid hormone levels	2.000000e-08
GCST001856_44	Thyroid hormone levels	2.000000e-14
GCST004131_21	Inflammatory bowel disease	5.000000e-36
GCST004132_11	Crohn’s disease	6.000000e-30
GCST004133_17	Ulcerative colitis	2.000000e-16
GCST004184_16	Lung function (FVC)	4.000000e-08
GCST006414_134	Atrial fibrillation	2.000000e-10
GCST008163_169	Height	1.000000e-07
GCST008164_3	Free thyroxine concentration	1.000000e-11
GCST008480_7	Lung function (FEV1)	3.000000e-08
GCST008482_5	Lung function (FVC)	6.000000e-14
GCST010002_282	Refractive error	1.000000e-14
GCST011741_38	LDL cholesterol levels in HIV infection	2.000000e-06
GCST90002392_603	Mean corpuscular volume	2.000000e-09
GCST90002403_249	Red blood cell count	1.000000e-11
GCST90020028_397	Hip circumference adjusted for BMI	3.000000e-09
GCST90020028_398	Hip circumference adjusted for BMI	3.000000e-11
GCST90020028_399	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_400	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004305	erythrocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D000568	Amenorrhea	C23.550.568.500
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
C567803	Pituitary Hormone Deficiency, Combined, 1 (supp.)
C536710	Winkelman Bethge Pfeiffer syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	2
Lead	affects methylation	2
aristolochic acid I	increases expression	1
apocarotenal	increases expression	1
arsenite	increases methylation	1
nutlin 3	affects cotreatment, increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Camptothecin	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	increases expression, affects cotreatment	1
Tetrachlorodibenzodioxin	increases expression	1
Triiodothyronine	decreases expression	1
Valproic Acid	increases methylation	1
Asbestos, Crocidolite	decreases methylation	1
Asbestos, Amosite	decreases methylation	1
beta Carotene	increases expression	1
Copper Sulfate	decreases expression	1
Permethrin	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_A3V3	SEES3-1V human LHX3, clone1	Embryonic stem cell	Male
CVCL_A3V4	SEES3-1V human LHX3, clone2	Embryonic stem cell	Male
CVCL_A3V5	SEES3-1V human LHX3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01103518	PHASE4	UNKNOWN	Ethinyl Estradiol and Cyproterone Acetate in Irregular Menstruation
NCT01206153	PHASE4	COMPLETED	Metformin for Treatment Antipsychotic Induced Amenorrhea in Female Schizophrenic Patients
NCT02393482	PHASE4	UNKNOWN	Psychological Impact of Amenorrhea in Women With Endometriosis
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT00827151	PHASE3	WITHDRAWN	Bone Mass Accrual in Adolescent Athletes
NCT00130117	PHASE2	COMPLETED	Study of Leptin for the Treatment of Hypothalamic Amenorrhea
NCT00152282	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of Asoprisnil and Estrogen Administration to Postmenopausal Women
NCT00196391	PHASE2	COMPLETED	A Trial to Evaluate DR-2021 in Women With Secondary Amenorrhea
NCT00383656	PHASE2	UNKNOWN	Pulsatile GnRH in Anovulatory Infertility
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT00881608	PHASE1	TERMINATED	Study to Evaluate Menses Induction in Women Administered Proellex
NCT07152730	PHASE1	WITHDRAWN	A Study to Measure Pharmacokinetic (PK) Concentrations of Gonadotropin-Releasing Hormone Delivered by the OmniPod Pump
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT03916978	PHASE2/PHASE3	RECRUITING	Autologous PRP Intra Ovarian Infusion to Restore Ovarian Function in Menopausal Women
NCT00556400	PHASE1/PHASE2	TERMINATED	Treatment of Menorrhagia in Women With Thrombocytopenia Using Platelets or Platelets and Hormones
NCT01187043	PHASE1/PHASE2	COMPLETED	Determination of the Lowest, Safe and Effective Dose of Proellex
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00011388	Not specified	COMPLETED	Reproductive Effects of Pesticide, PCB and Mercury Exposure in Laotian Immigrants
NCT00243607	Not specified	COMPLETED	Hydrotherapy Against Menopausal Symptoms in Breast Cancer Survivors
NCT00260286	Not specified	COMPLETED	Effects of Gynecological Age on LH Sensitivity to Energy Availability
NCT00456274	Not specified	UNKNOWN	Baselines in Reproductive Disorders
NCT00589654	Not specified	ACTIVE_NOT_RECRUITING	Menstrual Cycle Maintenance and Quality of Life: A Prospective Study
NCT01423487	Not specified	WITHDRAWN	Efficacy and Safety of Metformin in Preventing Patients With Risperidone From Weight Gain and Amenorrhea
NCT01500447	Not specified	RECRUITING	Inherited Reproductive Disorders
NCT01511588	Not specified	COMPLETED	Hormonal Regulation of Puberty and Fertility
NCT01785719	Not specified	COMPLETED	Evaluation of Ovarian Morphology and Function in Overweight Women During Weight Loss
NCT01927432	Not specified	COMPLETED	Ultrasound Characterization of Ovarian Follicle Dynamics in Women With Amenorrhea
NCT02224976	Not specified	COMPLETED	Effect of Intense Training on Ovarian Function and Bone Turnover
NCT04135729	Not specified	COMPLETED	Mental Health in Fitness Instructors
NCT04424576	Not specified	RECRUITING	Ovarian Morphology in Girls
NCT04938622	Not specified	COMPLETED	Bioenergetics of Exercise-Induced Menstrual Disturbances
NCT06280807	Not specified	RECRUITING	Observation of Environment and Reproductive-Endocrine Effects
NCT06800170	Not specified	RECRUITING	Treatment of Menstrual Cycle Alterations in Adolescents
NCT07015476	Not specified	RECRUITING	Retrospective Observational Evaluation of the Bone Mineral Density Outcome in Young Women With Amenorrhea
NCT07164248	Not specified	COMPLETED	Evaluation of Bone Mineral Density Indications and Outcomes in Female Adolescents: Implications for Early Detection of Osteopenia/Osteoporosis and Gynecologic Practice
NCT07612735	Not specified	NOT_YET_RECRUITING	Effects of Resistance Training on Women With Functional Hypothalamic Amenorrhea
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism