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9 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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LHFPL4
LHFPL tetraspan subfamily member 4
Chromosome 3 · 3p25.3
NCBI Gene: 375323Ensembl: ENSG00000156959.10HGNC: HGNC:29568UniProt: Q7Z7J7
11PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingGABA receptor bindingsensory perception of soundgamma-aminobutyric acid receptor clusteringesophageal diseaseneurodegenerative diseasegastroesophageal reflux diseaseliver disease
✦AI Summary

LHFPL4 (LHFPL tetraspan subfamily member 4) is a transmembrane protein that regulates inhibitory synapse formation and function. It acts as a traffic controller at the synapse by dictating neuroligin preference and enabling dynamic reassignment between excitatory and inhibitory postsynaptic domains 1. LHFPL4 maintains gamma-aminobutyric acid type A receptors (GABAARs) clustering and stabilizes their associated scaffold proteins at inhibitory synaptic sites, functioning in concert with neuroligin-2 (NLGN2) to recruit or stabilize GABAARs 2. This regulatory mechanism is critical for the molecular plasticity of inhibitory synapses, where LHFPL4 contributes to the dynamic equilibrium of synaptic binding sites and postsynaptic density organization 3. Beyond neurotransmission, LHFPL4 methylation patterns have been identified as epigenetic age-related markers in forensic applications, showing significant association with chr3 age in blood and buccal cell samples 45. Additionally, aberrant CpG island methylation of LHFPL4 has been identified as a novel methylation target in cervical cancer, occurring in 55% of cases and potentially relevant for early detection and risk prediction 6. These findings establish LHFPL4 as a multifunctional protein critical for synaptic inhibitory balance and as a biomarker for age estimation and cancer detection.

Sources cited
1
LHFPL4 (GARLH4) dictates neuroligin synapse-type preference through competitive hierarchy and enables dynamic reassignment between excitatory and inhibitory postsynaptic domains
PMID: 41481224
2
LHFPL4 is a transmembrane protein that interacts with GABAARs and modulates their trafficking and function as part of novel GABAAR transmembrane regulators
PMID: 33234346
3
LHFPL4 contributes to the molecular plasticity of inhibitory synapses through fractional occupancy of synaptic binding sites and dynamic equilibrium of postsynaptic density components
PMID: 30648560
4
LHFPL4 is a novel age-related DNA methylation marker in blood associated with chronological age
PMID: 31546163
5
LHFPL4 is used as an epigenetic age-prediction marker in combined tissue models for saliva and buccal cells
PMID: 36057238
6
LHFPL4 CpG island methylation is a novel methylation target in cervical cancer, methylated in 55% of cancers
PMID: 18381458
Disease Associationsⓘ20
esophageal diseaseOpen Targets
0.28Weak
neurodegenerative diseaseOpen Targets
0.25Weak
gastroesophageal reflux diseaseOpen Targets
0.19Weak
liver diseaseOpen Targets
0.13Weak
metabolic syndromeOpen Targets
0.09Suggestive
isolated asymptomatic elevation of creatine phosphokinaseOpen Targets
0.06Suggestive
type 2 diabetes mellitusOpen Targets
0.05Suggestive
pentosuriaOpen Targets
0.04Suggestive
pseudohyperaldosteronism type 2Open Targets
0.04Suggestive
diabetes mellitusOpen Targets
0.03Suggestive
non-neoplastic nevusOpen Targets
0.03Suggestive
colorectal cancerOpen Targets
0.03Suggestive
COVID-19Open Targets
0.02Suggestive
breast carcinomaOpen Targets
0.02Suggestive
generalized dystoniaOpen Targets
0.02Suggestive
renal osteodystrophyOpen Targets
0.02Suggestive
ataxia telangiectasiaOpen Targets
0.02Suggestive
ependymomaOpen Targets
0.02Suggestive
childhood supratentorial ependymomaOpen Targets
0.02Suggestive
non-small cell lung carcinomaOpen Targets
0.01Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
NLGN2Protein interaction93%GPHNProtein interaction52%GRXCR2Shared pathway50%CEACAM16Shared pathway50%LHFPL3Shared pathway50%CCDC50Shared pathway50%
Tissue Expression6 tissues
Brain
100%
Bone Marrow
3%
Ovary
0%
Liver
0%
Lung
0%
Heart
0%
Gene Interaction Network
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LHFPL4NLGN2GPHNGRXCR2CEACAM16LHFPL3CCDC50
PROTEIN STRUCTURE
Preparing viewer…
PDB9FAJ · 2.60 Å · EM
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.59Moderately Constrained
pLIⓘ
0.87Intermediate
Observed/Expected LoF0.30 [0.16–0.59]
RankingsWhere LHFPL4 stands among ~20K protein-coding genes
  • #16,811of 20,598
    Most Researched11
  • #4,038of 17,882
    Most Constrained (LOEUF)0.59 · top quartile
Genes detectedLHFPL4
Sources retrieved9 papers
Response time—
📄 Sources
9▼
1
PMID: 39637168
1.00
2
Epigenetic age estimation in saliva and in buccal cells.
PMID: 36057238
Forensic Sci Int Genet · 2022
0.89
3
Identifying blood-specific age-related DNA methylation markers on the Illumina MethylationEPIC® BeadChip.
PMID: 31546163
Forensic Sci Int · 2019
0.78
4
Identification of novel methylation markers in cervical cancer using restriction landmark genomic scanning.
PMID: 18381458
Cancer Res · 2008
0.67
5
Regulation of GABA
PMID: 33234346
Trends Neurosci · 2021
0.56