LHX5

Summary

LHX5 (LIM homeobox 5, HGNC:14216) is a protein-coding gene on chromosome 12q24.13, encoding LIM/homeobox protein Lhx5 (Q9H2C1). Plays an essential role in the regulation of neuronal differentiation and migration during development of the central nervous system.

This gene encodes a protein belonging to a large protein family, members of which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein may function as a transcriptional regulator and be involved in the control of differentiation and development of the forebrain. In mice, this protein is essential for the regulation of precursor cell proliferation and the control of neuronal differentiation and migration during hippocampal development. This protein is involved in learning and motor functions in adult mice.

Source: NCBI Gene 64211 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 44 total
• MANE Select transcript: NM_022363

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14216
Approved symbol	LHX5
Name	LIM homeobox 5
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000089116
Ensembl biotype	protein_coding
OMIM	605992
Entrez	64211

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000261731, ENST00000557836

RefSeq mRNA: 1 — MANE Select: NM_022363 NM_022363

CCDS: CCDS9171

Canonical transcript exons

ENST00000261731 — 5 exons

Exon	Start	End
ENSE00000563040	113467256	113467421
ENSE00000755547	113468127	113468404
ENSE00000755548	113469122	113469345
ENSE00000834995	113462033	113463557
ENSE00000834996	113471326	113471871

Expression profiles

Bgee: expression breadth broad, 30 present calls, max score 73.77.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8546 / max 82.7549, expressed in 116 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133368	0.6777	105
133367	0.1769	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	73.77	gold quality
medial globus pallidus	UBERON:0002477	67.02	gold quality
hypothalamus	UBERON:0001898	63.25	gold quality
tendon of biceps brachii	UBERON:0008188	62.12	gold quality
globus pallidus	UBERON:0001875	61.39	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.30	gold quality
cerebellar cortex	UBERON:0002129	59.71	gold quality
cerebellar hemisphere	UBERON:0002245	59.53	gold quality
cartilage tissue	UBERON:0002418	58.84	gold quality
cerebellum	UBERON:0002037	58.56	gold quality
heart right ventricle	UBERON:0002080	57.81	gold quality
parotid gland	UBERON:0001831	56.94	gold quality
inferior olivary complex	UBERON:0002127	54.81	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	54.56	gold quality
nasal cavity epithelium	UBERON:0005384	54.45	gold quality
body of stomach	UBERON:0001161	53.99	gold quality
myocardium	UBERON:0002349	52.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	52.50	gold quality
stomach	UBERON:0000945	50.84	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
nephron tubule	UBERON:0001231	47.50	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
Brodmann (1909) area 46	UBERON:0006483	47.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	46.87	gold quality
renal glomerulus	UBERON:0000074	46.86	gold quality
metanephric glomerulus	UBERON:0004736	46.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	46.47	gold quality
fundus of stomach	UBERON:0001160	46.22	gold quality
substantia nigra	UBERON:0002038	46.16	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8894	yes	419.68
E-HCAD-5	yes	409.33
E-ANND-3	no	1.14

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
GNRHR

JASPAR motifs

Motif	Name	Family
MA1519.1	LHX5	HD-LIM
MA1519.2	LHX5	HD-LIM

JASPAR matrix evidence (PMIDs): PMID:18585359

miRNA regulators (miRDB)

7 targeting LHX5, 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-9-5P	100.00	72.28	2361
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-6499-5P	87.01	61.21	38
HSA-MIR-579-5P	81.13	62.60	10

Literature-anchored findings (GeneRIF, showing 3)

• In mice, this protein is essential for the regulation of precursor cell proliferation and the control of neuronal differentiation and migration during hippocampal development. (PMID:10325223)
• In mice, this protein is involved in learning and motor functions. (PMID:11566211)
• Variation is not a highly penetrant autosomal dominant susceptibility locus for mood disorder in families. (PMID:12782966)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lhx5	ENSMUSG00000029595
rattus_norvegicus	Lhx5	ENSRNOG00000001392

Paralogs (20): FHL1 (ENSG00000022267), LMO3 (ENSG00000048540), ZFHX4 (ENSG00000091656), LHX2 (ENSG00000106689), LHX6 (ENSG00000106852), LHX3 (ENSG00000107187), 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 Lhx5 — Q9H2C1 (reviewed: Q9H2C1)

All UniProt accessions (1): Q9H2C1

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in the regulation of neuronal differentiation and migration during development of the central nervous system.

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal brain and in various regions of the adult central nervous system including the spinal cord, the thalamus, and the cerebellum.

RefSeq proteins (1): NP_071758* (*=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
IPR049618	Lhx1/5_LIM1	Domain
IPR049619	Lhx1/5_LIM2	Domain
IPR050453	LIM_Homeobox_TF	Family

Pfam: PF00046, PF00412

UniProt features (10 total): compositionally biased region 4, domain 2, region of interest 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2C1-F1	68.12	0.38

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 106 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, E2F4DP1_01, GOBP_CEREBELLAR_PURKINJE_CELL_LAYER_FORMATION, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_NEUROGENESIS, FOXO1_01, CHX10_01, GOBP_CELL_PROLIFERATION_IN_FOREBRAIN, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, GOBP_FOREBRAIN_GENERATION_OF_NEURONS

GO Biological Process (15): regulation of transcription by RNA polymerase II (GO:0006357), neuroblast proliferation (GO:0007405), spinal cord association neuron differentiation (GO:0021527), cerebellar Purkinje cell differentiation (GO:0021702), hippocampus development (GO:0021766), cell proliferation in forebrain (GO:0021846), forebrain neuron differentiation (GO:0021879), regulation of cerebellar granule cell precursor proliferation (GO:0021936), cerebellar Purkinje cell-granule cell precursor cell signaling (GO:0021937), neuron differentiation (GO:0030182), positive regulation of DNA-templated transcription (GO:0045893), regulation of neuroblast proliferation (GO:1902692), regulation of DNA-templated transcription (GO:0006355), cell-cell signaling (GO:0007267), cerebellum development (GO:0021549)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), zinc ion binding (GO:0008270), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565), metal ion binding (GO:0046872)

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
central nervous system neuron differentiation	3
regulation of DNA-templated transcription	2
generation of neurons	2
neural precursor cell proliferation	2
anatomical structure development	2
regulation of neural precursor cell proliferation	2
DNA-templated transcription	2
transcription by RNA polymerase II	1
cell differentiation in spinal cord	1
dorsal spinal cord development	1
cell differentiation in hindbrain	1
cerebellar Purkinje cell layer formation	1
pallium development	1
limbic system development	1
forebrain development	1
forebrain generation of neurons	1
cerebellar granule cell precursor proliferation	1
cell-cell signaling	1
cell differentiation	1
positive regulation of RNA biosynthetic process	1
neuroblast proliferation	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell communication	1
signaling	1
metencephalon development	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
transition metal ion binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
cation binding	1
chromosome	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHX5	BARHL1	Q9BZE3	619
LHX5	DBX1	A6NMT0	552
LHX5	PAX2	Q02962	522
LHX5	LDB1	Q86U70	522
LHX5	EMX2	Q04743	518
LHX5	FEZF1	A0PJY2	503
LHX5	PTF1A	Q7RTS3	494
LHX5	SIX3	O95343	481
LHX5	EMX1	Q04741	478
LHX5	LDB2	O43679	477
LHX5	NKX2-1	P43699	476
LHX5	RAB2A	P08886	475
LHX5	FOXB1	Q99853	473
LHX5	BARHL2	Q9NY43	461
LHX5	FOXG1	P55315	460

IntAct

92 interactions, top by confidence:

A	B	Type	Score
CASP6	LHX5	psi-mi:“MI:0915”(physical association)	0.560
CCK	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LHX5	DMWD	psi-mi:“MI:0915”(physical association)	0.560
LHX5		psi-mi:“MI:0915”(physical association)	0.560
LHX5	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LHX5	GSN	psi-mi:“MI:0915”(physical association)	0.560
LHX5	HIP1	psi-mi:“MI:0915”(physical association)	0.560
HLA-A	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LHX5	PMP22	psi-mi:“MI:0915”(physical association)	0.560
PPIB	LHX5	psi-mi:“MI:0915”(physical association)	0.560
RAN	LHX5	psi-mi:“MI:0915”(physical association)	0.560
TSC1	LHX5	psi-mi:“MI:0915”(physical association)	0.560
UQCRC2	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LHX5	YWHAG	psi-mi:“MI:0915”(physical association)	0.560
LHX5	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
LHX5	KAT5	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	LHX5	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	LHX5	psi-mi:“MI:0915”(physical association)	0.560
PEX26	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LMO3	LHX5	psi-mi:“MI:0915”(physical association)	0.560
LHX5	COQ8A	psi-mi:“MI:0915”(physical association)	0.560
LHX5	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
SNCA	LHX5	psi-mi:“MI:0915”(physical association)	0.560
HTT	LHX5	psi-mi:“MI:0915”(physical association)	0.560

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

812 predictions. Top by Δscore:

Variant	Effect	Δscore
12:113467417:CACAC:C	acceptor_gain	1.0000
12:113467419:CAC:C	acceptor_gain	1.0000
12:113468121:CCGCA:C	donor_loss	1.0000
12:113468122:CGCA:C	donor_loss	1.0000
12:113468123:GCACC:G	donor_loss	1.0000
12:113468124:CA:C	donor_loss	1.0000
12:113468125:A:AT	donor_loss	1.0000
12:113468126:C:CT	donor_loss	1.0000
12:113468401:GACA:G	acceptor_gain	1.0000
12:113468405:C:CC	acceptor_gain	1.0000
12:113468412:C:CT	acceptor_gain	1.0000
12:113468421:C:CT	acceptor_gain	1.0000
12:113468422:G:T	acceptor_gain	1.0000
12:113469116:TCCTA:T	donor_loss	1.0000
12:113469117:CCTAC:C	donor_loss	1.0000
12:113469118:CTA:C	donor_loss	1.0000
12:113469119:TACC:T	donor_loss	1.0000
12:113469120:A:AC	donor_gain	1.0000
12:113469120:A:T	donor_loss	1.0000
12:113469121:C:CC	donor_gain	1.0000
12:113469121:C:CG	donor_loss	1.0000
12:113469139:T:TA	donor_gain	1.0000
12:113469341:AGCGC:A	acceptor_gain	1.0000
12:113469342:GCGC:G	acceptor_gain	1.0000
12:113469343:CGC:C	acceptor_gain	1.0000
12:113469343:CGCC:C	acceptor_gain	1.0000
12:113469344:GC:G	acceptor_gain	1.0000
12:113469344:GCCTG:G	acceptor_loss	1.0000
12:113469345:CC:C	acceptor_gain	1.0000
12:113469345:CCT:C	acceptor_loss	1.0000

AlphaMissense

2641 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:113467387:C:A	R237L	1.000
12:113467387:C:G	R237P	1.000
12:113467387:C:T	R237Q	1.000
12:113467388:G:A	R237W	1.000
12:113467388:G:C	R237G	1.000
12:113467390:C:G	R236P	1.000
12:113467390:C:T	R236H	1.000
12:113467391:G:A	R236C	1.000
12:113467391:G:T	R236S	1.000
12:113467394:C:T	E235K	1.000
12:113467395:T:A	K234N	1.000
12:113467395:T:G	K234N	1.000
12:113467396:T:A	K234I	1.000
12:113467396:T:G	K234T	1.000
12:113467397:T:C	K234E	1.000
12:113467397:T:G	K234Q	1.000
12:113467399:G:A	S233F	1.000
12:113467399:G:T	S233Y	1.000
12:113467400:A:G	S233P	1.000
12:113467402:C:A	R232L	1.000
12:113467402:C:G	R232P	1.000
12:113467402:C:T	R232Q	1.000
12:113467403:G:A	R232W	1.000
12:113467403:G:C	R232G	1.000
12:113467405:C:A	R231L	1.000
12:113467405:C:G	R231P	1.000
12:113467406:G:C	R231G	1.000
12:113467407:G:C	N230K	1.000
12:113467407:G:T	N230K	1.000
12:113467408:T:A	N230I	1.000

dbSNP variants (sampled 300 via entrez): RS1000011920 (12:113471931 G>A,C), RS1000164313 (12:113468584 C>G), RS1000322803 (12:113469028 A>C,G), RS1000346175 (12:113462872 C>A,T), RS1000762607 (12:113462000 A>G), RS1000816951 (12:113461708 T>A,C), RS1000863871 (12:113463063 G>C), RS1000993996 (12:113467574 G>A,C,T), RS1001548395 (12:113473411 T>G), RS1001665988 (12:113464683 T>G), RS1001780092 (12:113468554 C>T), RS1002263753 (12:113465987 A>C,T), RS1002367946 (12:113462752 G>A), RS1002507865 (12:113472687 C>G,T), RS1002635674 (12:113467096 G>C)

Disease associations

OMIM: gene MIM:605992 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003074_26	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	1.000000e-06
GCST003139_18	Glomerular filtration rate in chronic kidney disease	3.000000e-06
GCST005951_2	Body mass index	9.000000e-09
GCST006218_24	Erosive tooth wear (severe vs non-severe)	1.000000e-08
GCST009391_1092	Metabolite levels	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004340	body mass index
EFO:0010543	uridine diphosphate galactose measurement
EFO:0010544	uridine diphosphate glucose measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
trichostatin A	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	increases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A3V9	SEES3-1V human LHX5, clone1	Embryonic stem cell	Male
CVCL_A3W0	SEES3-1V human LHX5, clone2	Embryonic stem cell	Male
CVCL_A3W1	SEES3-1V human LHX5, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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