LHFPL4

Summary

LHFPL4 (LHFPL tetraspan subfamily member 4, HGNC:29568) is a protein-coding gene on chromosome 3p25.3, encoding LHFPL tetraspan subfamily member 4 protein (Q7Z7J7). Plays a role in the regulation of inhibitory synapse formation and function by being involved in maintening gamma-aminobutyric acid receptors (GABAARs) clustering and their associated scaffold proteins at inhibitory synaptic sites.

This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in one LHFP-like gene result in deafness in humans and mice, and a second LHFP-like gene is fused to a high-mobility group gene in a translocation-associated lipoma.

Source: NCBI Gene 375323 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 26 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_198560

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29568
Approved symbol	LHFPL4
Name	LHFPL tetraspan subfamily member 4
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	GARLH4
Ensembl gene	ENSG00000156959
Ensembl biotype	protein_coding
OMIM	610240
Entrez	375323

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000287585, ENST00000495730, ENST00000498277, ENST00000854959, ENST00000934547, ENST00000934548, ENST00000934549

RefSeq mRNA: 1 — MANE Select: NM_198560 NM_198560

CCDS: CCDS33691

Canonical transcript exons

ENST00000287585 — 4 exons

Exon	Start	End
ENSE00001029323	9552274	9552847
ENSE00001340607	9553685	9553822
ENSE00001505112	9505967	9506203
ENSE00003325974	9498361	9502311

Expression profiles

Bgee: expression breadth ubiquitous, 109 present calls, max score 89.64.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1132 / max 76.0098, expressed in 271 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40972	1.9712	269
40973	0.0872	59
40974	0.0548	38

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	89.64	gold quality
cortical plate	UBERON:0005343	89.59	gold quality
postcentral gyrus	UBERON:0002581	88.55	gold quality
superior frontal gyrus	UBERON:0002661	87.90	gold quality
endothelial cell	CL:0000115	87.42	gold quality
middle temporal gyrus	UBERON:0002771	87.33	gold quality
parietal lobe	UBERON:0001872	87.29	gold quality
entorhinal cortex	UBERON:0002728	87.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.77	gold quality
prefrontal cortex	UBERON:0000451	85.54	gold quality
frontal cortex	UBERON:0001870	85.16	gold quality
primary visual cortex	UBERON:0002436	84.89	gold quality
neocortex	UBERON:0001950	84.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.33	gold quality
cerebellum	UBERON:0002037	84.06	gold quality
cerebellar cortex	UBERON:0002129	84.03	gold quality
cerebral cortex	UBERON:0000956	84.01	gold quality
cerebellar hemisphere	UBERON:0002245	83.94	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.68	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.64	gold quality
right frontal lobe	UBERON:0002810	83.38	gold quality
occipital lobe	UBERON:0002021	83.30	gold quality
upper arm skin	UBERON:0004263	82.68	gold quality
temporal lobe	UBERON:0001871	82.36	gold quality
anterior cingulate cortex	UBERON:0009835	82.36	gold quality
hypothalamus	UBERON:0001898	82.28	gold quality
forebrain	UBERON:0001890	82.24	gold quality
brain	UBERON:0000955	82.15	gold quality
Ammon’s horn	UBERON:0001954	81.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

143 targeting LHFPL4, 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-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641

Literature-anchored findings (GeneRIF, showing 1)

• The authors present an overview of the LHFP gene family in mouse and humans (PMID:15905332)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lhfpl4a	ENSDARG00000111810
mus_musculus	Lhfpl4	ENSMUSG00000042873
rattus_norvegicus	Lhfpl4	ENSRNOG00000091268
drosophila_melanogaster	Tmhs	FBGN0262624

Paralogs (6): LHFPL2 (ENSG00000145685), LHFPL1 (ENSG00000182508), LHFPL6 (ENSG00000183722), LHFPL3 (ENSG00000187416), LHFPL5 (ENSG00000197753), LHFPL7 (ENSG00000206069)

Protein

Protein identifiers

LHFPL tetraspan subfamily member 4 protein — Q7Z7J7 (reviewed: Q7Z7J7)

Alternative names: GABAA receptor regulatory Lhfpl4, Lipoma HMGIC fusion partner-like 4 protein

All UniProt accessions (1): Q7Z7J7

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the regulation of inhibitory synapse formation and function by being involved in maintening gamma-aminobutyric acid receptors (GABAARs) clustering and their associated scaffold proteins at inhibitory synaptic sites. Acts in concert with NLGN2 to recruit or stabilize GABAARs.

Subunit / interactions. Interacts with GABA(A) receptor subunits. Identified in a complex of 720 kDa composed of LHFPL4, NLGN2, GABRA1, GABRB2, GABRG2 and GABRB3. Interacts with GABRB3. Interacts with GABRA2. Interacts with GABRG2. Interacts with GABRA1. Interacts with NLGN2; leading to mutual regulation of protein level and synaptic clustering.

Subcellular location. Cell projection. Dendrite. Postsynaptic cell membrane.

Similarity. Belongs to the LHFP family.

RefSeq proteins (1): NP_940962* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019372	LHFPL	Family

Pfam: PF10242

UniProt features (5 total): transmembrane region 4, chain 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
9FAJ	ELECTRON MICROSCOPY	2.6
9FAK	ELECTRON MICROSCOPY	2.6
9FAP	ELECTRON MICROSCOPY	2.8
9FAN	ELECTRON MICROSCOPY	2.9
9FAQ	ELECTRON MICROSCOPY	2.9
9FAR	ELECTRON MICROSCOPY	2.9
9FAW	ELECTRON MICROSCOPY	2.9
9FAX	ELECTRON MICROSCOPY	2.9
9FAU	ELECTRON MICROSCOPY	3.1
9FAV	ELECTRON MICROSCOPY	3.2
9FAM	ELECTRON MICROSCOPY	3.5
9FAT	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z7J7-F1	83.21	0.50

Antibody-complex structures (SAbDab): 9 — 9FAJ, 9FAK, 9FAM, 9FAP, 9FAQ, 9FAT, 9FAU, 9FAW, 9FAX

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_SYNAPSE_ASSEMBLY, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_POSTSYNAPTIC_MEMBRANE_ORGANIZATION, GOBP_REGULATION_OF_SYNAPSE_STRUCTURE_OR_ACTIVITY, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_SENSORY_PERCEPTION, GOBP_CELL_JUNCTION_ASSEMBLY, GOCC_NEURON_PROJECTION

GO Biological Process (4): sensory perception of sound (GO:0007605), gamma-aminobutyric acid receptor clustering (GO:0097112), neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0099645), regulation of inhibitory synapse assembly (GO:1905702)

GO Molecular Function (2): GABA receptor binding (GO:0050811), protein binding (GO:0005515)

GO Cellular Component (9): plasma membrane (GO:0005886), dendrite (GO:0030425), postsynaptic membrane (GO:0045211), inhibitory synapse (GO:0060077), GABA-ergic synapse (GO:0098982), postsynaptic specialization (GO:0099572), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
postsynapse	2
synapse	2
cellular anatomical structure	2
sensory perception of mechanical stimulus	1
postsynaptic membrane organization	1
neurotransmitter-gated ion channel clustering	1
protein-containing complex localization	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
protein localization to postsynaptic specialization membrane	1
regulation of synapse assembly	1
inhibitory synapse assembly	1
signaling receptor binding	1
binding	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
synaptic membrane	1
organelle	1
cell junction	1

Protein interactions and networks

STRING

1324 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LHFPL4	NLGN2	Q8NFZ4	925
LHFPL4	GPHN	Q9NQX3	753
LHFPL4	THUMPD3	Q9BV44	585
LHFPL4	NLGN1	Q8N2Q7	546
LHFPL4	TMEM121B	Q9BXQ6	543
LHFPL4	NLGN3	Q9NZ94	527
LHFPL4	NOL4	O94818	513
LHFPL4	INSYN1	Q2T9L4	496
LHFPL4	ZNF507	Q8TCN5	493
LHFPL4	SETD5	Q9C0A6	492
LHFPL4	IGSF9B	Q9UPX0	464
LHFPL4	AGAP3	Q96P47	462
LHFPL4	NLGN4Y	Q8NFZ3	457
LHFPL4	NLGN4X	Q8N0W4	451
LHFPL4	ARHGEF9	O43307	433

IntAct

7 interactions, top by confidence:

A	B	Type	Score
LHFPL4	TEX264	psi-mi:“MI:0915”(physical association)	0.560
LHFPL4	IFNA17	psi-mi:“MI:0914”(association)	0.530
LHFPL4	ATP5F1B	psi-mi:“MI:0914”(association)	0.530
TEX264	LHFPL4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): IFNA17 (Affinity Capture-MS), RABIF (Affinity Capture-MS), ATP5B (Affinity Capture-MS), FKRP (Affinity Capture-MS), TEX264 (Two-hybrid), C16orf54 (Affinity Capture-MS), IFNA17 (Affinity Capture-MS), LCP1 (Affinity Capture-MS), ZYG11B (Affinity Capture-MS), STOM (Affinity Capture-MS), GPX4 (Affinity Capture-MS), CRACR2A (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), C17orf75 (Affinity Capture-MS), YTHDF1 (Affinity Capture-MS)

ESM2 similar proteins: A4IFN5, A6NDV4, B1AWJ5, B1AZA5, B2LYG4, P59266, Q05B45, Q0VCJ8, Q3KRC4, Q3UMZ3, Q5EA70, Q5H8A4, Q5QJU3, Q5RBJ7, Q5U3C3, Q5VTY9, Q5ZMH6, Q6PHN7, Q6TCH4, Q6W5G4, Q6ZVK1, Q7Z7J7, Q865K8, Q86WK9, Q8BHH9, Q8BMT9, Q8BWB6, Q8C1E7, Q8K3J9, Q8N6M3, Q8NBT3, Q8NEB5, Q8NFT2, Q8VCW4, Q8VCY8, Q8VD53, Q8VDI9, Q96GM1, Q9BSA9, Q9BXJ8

Diamond homologs: Q17R16, Q4KL25, Q5PPI7, Q5U4E0, Q66IV3, Q6DHB5, Q7TSY2, Q7Z7J7, Q7ZZL8, Q86UP9, Q8TAF8, Q9CTN8, Q5BJS2, Q8BM86, Q9Y693

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	19
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3391878	GRCh37/hg19 3p25.3(chr3:9506164-9561205)x1	Pathogenic
442033	GRCh37/hg19 3p25.3(chr3:9421663-9574327)x1	Likely pathogenic

SpliceAI

676 predictions. Top by Δscore:

Variant	Effect	Δscore
3:9506232:C:CT	acceptor_gain	1.0000
3:9506238:C:CT	acceptor_gain	1.0000
3:9506239:A:T	acceptor_gain	1.0000
3:9505990:T:TA	donor_gain	0.9900
3:9506199:CAGAG:C	acceptor_gain	0.9900
3:9506229:C:CT	acceptor_gain	0.9900
3:9506232:C:T	acceptor_gain	0.9900
3:9506234:C:CT	acceptor_gain	0.9900
3:9506235:G:T	acceptor_gain	0.9900
3:9552268:CCCTA:C	donor_loss	0.9900
3:9552269:CCTA:C	donor_loss	0.9900
3:9552270:CTA:C	donor_loss	0.9900
3:9552271:TA:T	donor_loss	0.9900
3:9552272:A:AT	donor_loss	0.9900
3:9552273:C:CA	donor_loss	0.9900
3:9552276:G:A	donor_gain	0.9900
3:9552304:TGTAG:T	donor_gain	0.9900
3:9553680:CCAA:C	donor_loss	0.9900
3:9553681:CAA:C	donor_loss	0.9900
3:9553682:AACC:A	donor_loss	0.9900
3:9553683:A:T	donor_loss	0.9900
3:9553684:C:CG	donor_loss	0.9900
3:9505961:A:AC	donor_gain	0.9800
3:9505962:C:CC	donor_gain	0.9800
3:9505966:C:CA	donor_gain	0.9800
3:9506200:AGAGC:A	acceptor_loss	0.9800
3:9506201:GAG:G	acceptor_gain	0.9800
3:9506202:AGCT:A	acceptor_loss	0.9800
3:9506203:GCTG:G	acceptor_loss	0.9800
3:9506204:C:CC	acceptor_gain	0.9800

AlphaMissense

1605 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:9506087:A:G	W175R	1.000
3:9506087:A:T	W175R	1.000
3:9506162:A:G	W150R	1.000
3:9506162:A:T	W150R	1.000
3:9552542:C:A	W46C	1.000
3:9552542:C:G	W46C	1.000
3:9552544:A:G	W46R	1.000
3:9552544:A:T	W46R	1.000
3:9552604:A:G	W26R	1.000
3:9552604:A:T	W26R	1.000
3:9506063:C:G	G183R	0.999
3:9506085:C:A	W175C	0.999
3:9506085:C:G	W175C	0.999
3:9506097:A:C	C171W	0.999
3:9506098:C:G	C171S	0.999
3:9506098:C:T	C171Y	0.999
3:9506099:A:G	C171R	0.999
3:9506099:A:T	C171S	0.999
3:9506133:A:C	C159W	0.999
3:9506134:C:G	C159S	0.999
3:9506134:C:T	C159Y	0.999
3:9506135:A:T	C159S	0.999
3:9506160:C:A	W150C	0.999
3:9506160:C:G	W150C	0.999
3:9506170:G:T	P147H	0.999
3:9506186:C:G	G142R	0.999
3:9552296:G:C	C128W	0.999
3:9552501:C:A	G60V	0.999
3:9552501:C:T	G60D	0.999
3:9552502:C:G	G60R	0.999

dbSNP variants (sampled 300 via entrez): RS1000042706 (3:9549611 C>T), RS1000068565 (3:9545912 TAAAAG>T), RS1000100376 (3:9555665 C>G,T), RS1000110960 (3:9548400 C>G), RS1000146090 (3:9512147 G>A), RS1000147070 (3:9502130 A>C,G), RS1000182493 (3:9527918 A>G), RS1000231853 (3:9538411 C>G,T), RS1000284813 (3:9533385 G>A,T), RS1000324108 (3:9543436 C>G,T), RS1000358939 (3:9533069 G>A), RS1000389575 (3:9518779 C>A,T), RS1000399084 (3:9507064 C>T), RS1000503943 (3:9517157 TTTG>T), RS1000520039 (3:9549336 C>A)

Disease associations

OMIM: gene MIM:610240 | disease phenotypes: MIM:615761

GenCC curated gene-disease

Mondo (1): intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (MONDO:0014336)

Orphanet (1): OBSOLETE: Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency (Orphanet:404440)

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
mercuric bromide	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Atrazine	increases expression	1
Cadmium	decreases expression, increases abundance	1
Diethylhexyl Phthalate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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