GeneBe

LHX3

protein-coding

LIM homeobox 3, the group of LIM class homeoboxes

Gene summary

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. [provided by RefSeq, Dec 2015]

MANE transcript

NM_178138.6

Inheritance

AD, AR

ClinVar variants

P:43U:160B:238

Top phenotype

Pituitary hormone deficiency, combined, 3

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr9:136,196,250-136,205,128

External References & Databases

Ensembl (ENSG00000107187)NCBI Gene (8022)OMIM (600577)HGNC:6595GenCCUniProt (Q9UBR4)AlphaFoldClinVar (LHX3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~8.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypothyroidism due to deficient transcription factors involved in pituitary development or functionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016411

Submitter: Orphanet

non-acquired combined pituitary hormone deficiency with spine abnormalitiesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009091

Submitter: Natera

non-acquired combined pituitary hormone deficiency with spine abnormalitiesSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009091

Submitter: Orphanet

non-acquired combined pituitary hormone deficiency with spine abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009091

Submitter: Labcorp Genetics (formerly Invitae)

non-acquired combined pituitary hormone deficiency with spine abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009091

Submitter: PanelApp Australia

non-acquired combined pituitary hormone deficiency with spine abnormalitiesDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009091

Submitter: G2P

Clinical Genomic Database (CGD)

Pituitary hormone deficiency, combined, 3AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic; Endocrine

Rationale: Medical treatment of endocrine deficiencies, which can include congenital hypothyroidism and ACTH deficiency, can be beneficial; Awareness of hearing impairment can allow prompt interventions related to speech and language development

Refs: 10835633; 16394081; 17327381; 18407919; 22238406; 22286346Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LHX3 variants in ClinVar

9 Conditions Cataloged
not providedTotal: 428
Non-acquired combined pituitary hormone deficiency with spine abnormalitiesTotal: 118
Inborn genetic diseasesTotal: 84
not specifiedTotal: 57
LHX3-related disorderTotal: 34
Combined pituitary hormone deficiencies, genetic formTotal: 20
Pituitary hormone deficiency, combined, 1Total: 3
Congenital hypothyroidismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178138.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
230
clinvar
 235
missense
1
clinvar
2
clinvar
152
clinvar
8
clinvar
 163
nonsense
8
clinvar
7
clinvar
 15
start loss
0
frameshift
4
clinvar
8
clinvar
3
clinvar
 15
splice donor/acceptor (+/-2bp)
3
clinvar
10
clinvar
 13
Total16271602380441

Highest pathogenic variant AF is 0.000048404992

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_178138.6RefSeqNP_835258.16MANE Select
ENST00000371748.10EnsemblENSP00000360813.46MANE Select
NM_001363746.1RefSeqNP_001350675.16Standard
NM_014564.5RefSeqNP_055379.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Developmental Biology
  • Regulation of expression of SLITs and ROBOs
  • Signaling by ROBO receptors
  • Axon guidance

Biological Process

  • placenta development
  • motor neuron axon guidance
  • animal organ morphogenesis
  • spinal cord motor neuron cell fate specification
  • ventral spinal cord interneuron specification

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • RNA polymerase II transcription factor binding
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • sequence-specific DNA binding

Cellular Component

  • nucleus
  • transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000371746
Coding exons
6
Length
8860
Individuals with no LoFs
125490
Homozygous LoFs
0
Heterozygous LoFs
10
Defined
125500
p
0.0000398
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.3332182320.9380.00001122532
Missense (PolyPhen)6877.2330.88045821
Synonymous0.09361041050.9880.00000534831
Loss of Function2.31616.00.3767.38e-7176

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000310.000029rare
Ashkenazi Jewish00.0absent
East Asian0.0000540.000054rare
Finnish0.0000520.000046rare
European (Non-Finnish)0.0000550.000053rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as a transcriptional activator. Binds to and activates the promoter of the alpha-glycoprotein gene, and synergistically enhances transcription from the prolactin promoter in cooperation with POU1F1/Pit-1 (By similarity). 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. {ECO:0000250, ECO:0000269|PubMed:21149718}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:10835633, ECO:0000269|PubMed:17327381, ECO:0000269|PubMed:28302169}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.257

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.795

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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