LRCH4

Summary

LRCH4 (leucine rich repeats and calponin homology domain containing 4, HGNC:6691) is a protein-coding gene on chromosome 7q22.1, encoding Leucine-rich repeat and calponin homology domain-containing protein 4 (O75427). Accessory protein that regulates signaling by multiple TLRs, acting as a broad-spanning regulator of the innate immune response.

This gene encodes a protein that contains leucine-rich repeats (LRR) at its amino terminus and that is known to be involved in ligand binding. The carboxyl terminus may act as a membrane anchor. Identified structural elements suggest that the encoded protein resembles a receptor.

Source: NCBI Gene 4034 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 154 total — 1 pathogenic
• MANE Select transcript: NM_002319

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6691
Approved symbol	LRCH4
Name	leucine rich repeats and calponin homology domain containing 4
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000077454
Ensembl biotype	protein_coding
OMIM	620165
Entrez	4034

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 19 protein_coding, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000310300, ENST00000467201, ENST00000470184, ENST00000476881, ENST00000485554, ENST00000485583, ENST00000487697, ENST00000490359, ENST00000497245, ENST00000498539, ENST00000877641, ENST00000877642, ENST00000877643, ENST00000877644, ENST00000877645, ENST00000877646, ENST00000877647, ENST00000877648, ENST00000877649, ENST00000877650, ENST00000877651, ENST00000913367, ENST00000913368, ENST00000913369, ENST00000965051, ENST00000965052, ENST00000965053

RefSeq mRNA: 2 — MANE Select: NM_002319 NM_001289934, NM_002319

CCDS: CCDS34706, CCDS94156

Canonical transcript exons

ENST00000310300 — 18 exons

Exon	Start	End
ENSE00000710709	100585881	100586129
ENSE00002431243	100576694	100576777
ENSE00002447667	100576902	100577005
ENSE00003492939	100575871	100576008
ENSE00003495490	100575705	100575782
ENSE00003511792	100577822	100577912
ENSE00003543517	100581777	100581882
ENSE00003549698	100582041	100582167
ENSE00003569652	100577497	100577558
ENSE00003571414	100582315	100582459
ENSE00003591939	100577664	100577740
ENSE00003600595	100578159	100578258
ENSE00003613563	100578399	100578511
ENSE00003613702	100578650	100578786
ENSE00003633122	100577273	100577389
ENSE00003660067	100576238	100576323
ENSE00003680140	100577086	100577154
ENSE00003846915	100574011	100575304

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 98.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.4321 / max 572.6308, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
85217	33.5912	1817
85218	0.4994	235
85216	0.2337	103
85215	0.1077	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.90	gold quality
right testis	UBERON:0004534	98.57	gold quality
left testis	UBERON:0004533	98.54	gold quality
blood	UBERON:0000178	98.40	gold quality
spleen	UBERON:0002106	97.86	gold quality
pituitary gland	UBERON:0000007	97.02	gold quality
leukocyte	CL:0000738	96.98	gold quality
testis	UBERON:0000473	96.98	gold quality
monocyte	CL:0000576	96.96	gold quality
right ovary	UBERON:0002118	96.86	gold quality
left ovary	UBERON:0002119	96.86	gold quality
metanephros cortex	UBERON:0010533	96.79	gold quality
adenohypophysis	UBERON:0002196	96.66	gold quality
right lobe of thyroid gland	UBERON:0001119	96.59	gold quality
left lobe of thyroid gland	UBERON:0001120	96.39	gold quality
right lung	UBERON:0002167	96.33	gold quality
ovary	UBERON:0000992	96.15	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.08	gold quality
nerve	UBERON:0001021	96.01	gold quality
tibial nerve	UBERON:0001323	96.01	gold quality
vermiform appendix	UBERON:0001154	95.99	gold quality
thyroid gland	UBERON:0002046	95.94	gold quality
bone marrow	UBERON:0002371	95.91	gold quality
minor salivary gland	UBERON:0001830	95.83	gold quality
lymph node	UBERON:0000029	95.74	gold quality
saliva-secreting gland	UBERON:0001044	95.72	gold quality
upper lobe of left lung	UBERON:0008952	95.67	gold quality
right uterine tube	UBERON:0001302	95.62	gold quality
left uterine tube	UBERON:0001303	95.61	gold quality
right adrenal gland cortex	UBERON:0035827	95.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

78 targeting LRCH4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4510	100.00	66.60	2050
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-8485	100.00	77.57	4731
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-605-3P	99.88	69.22	1833
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-320A-3P	99.77	69.73	2107

Literature-anchored findings (GeneRIF, showing 1)

• Using two bioinformatics pipelines for analysis of RNA fingerprints we identified significant effects of E. coli on the mRNAs HMBS, ATP2C1 and LRCH4. To see whether these three proteins were present in platelets and were influenced by the bacteria, we analysed HMBS, ATP2C1 and LRCH4 in platelet lysates and releasates by Western blot and ELISA. (PMID:30385858)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lrch4	ENSMUSG00000093445
rattus_norvegicus	Lrch4	ENSRNOG00000001402

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), SCRIB (ENSG00000180900), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

Leucine-rich repeat and calponin homology domain-containing protein 4 — O75427 (reviewed: O75427)

Alternative names: Leucine-rich repeat neuronal protein 4

All UniProt accessions (2): O75427, H7C5D9

UniProt curated annotations — full annotation on UniProt →

Function. Accessory protein that regulates signaling by multiple TLRs, acting as a broad-spanning regulator of the innate immune response. In macrophages, binds LPS and promotes proper docking of LPS in lipid raft membrane. May be required for lipid raft maintenance.

Subcellular location. Cell membrane.

RefSeq proteins (2): NP_001276863, NP_002310* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR001715	CH_dom	Domain
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR050216	LRR_domain-containing	Family

Pfam: PF00307, PF13855

UniProt features (41 total): modified residue 13, repeat 9, compositionally biased region 7, region of interest 4, sequence conflict 4, chain 1, transmembrane region 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75427-F1	64.98	0.25

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 (13): 279, 281, 304, 307, 309, 313, 432, 457, 511, 513, 517, 521, 589

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 366 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, RNGTGGGC_UNKNOWN, MCLACHLAN_DENTAL_CARIES_UP, GOBP_SYNAPSE_ASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, MODULE_45, AREB6_03, AAGCCAT_MIR135A_MIR135B, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY

GO Biological Process (3): membrane raft assembly (GO:0001765), nervous system development (GO:0007399), positive regulation of toll-like receptor signaling pathway (GO:0034123)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), PML body (GO:0016605), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane raft organization	1
membrane assembly	1
system development	1
toll-like receptor signaling pathway	1
regulation of toll-like receptor signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
nuclear body	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1680 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRCH4	PMS2P11	Q13670	496
LRCH4	LRRC4	Q9HBW1	476
LRCH4	AGFG2	O95081	443
LRCH4	LRRC4C	Q9HCJ2	439
LRCH4	LRRN3	Q9H3W5	435
LRCH4	LRRN2	O75325	433
LRCH4	SUMF1	Q8NBK3	420
LRCH4	ANKRD46	Q86W74	403
LRCH4	CNTN4	Q8IWV2	400
LRCH4	ACAP1	Q15027	394
LRCH4	LRCH1	Q9Y2L9	389
LRCH4	GNB2	P11016	385
LRCH4	HTR2C	P28335	373
LRCH4	NUDT6	P53370	373
LRCH4	LRRC3B	Q96PB8	349

IntAct

72 interactions, top by confidence:

A	B	Type	Score
DOCK8	LRCH4	psi-mi:“MI:0914”(association)	0.620
MDFI	LRCH4	psi-mi:“MI:0915”(physical association)	0.620
DOCK8	LRCH4	psi-mi:“MI:0403”(colocalization)	0.620
LRCH4	MDFI	psi-mi:“MI:0915”(physical association)	0.620
LRCH4	KRTAP10-7	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	KRT40	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	NOTCH2NLA	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	LRCH4	psi-mi:“MI:0915”(physical association)	0.560
KRT40	LRCH4	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	LRCH4	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	RETREG3	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	KASH5	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	HSD17B11	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	CYB5R3	psi-mi:“MI:0915”(physical association)	0.560
ELOVL7	LRCH4	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	RNASEK	psi-mi:“MI:0915”(physical association)	0.560
DOCK7	LRCH4	psi-mi:“MI:0915”(physical association)	0.560
LRCH4	DOCK7	psi-mi:“MI:0914”(association)	0.560
LRCH4	RTN4	psi-mi:“MI:0915”(physical association)	0.550
LRCH4	DOCK6	psi-mi:“MI:0915”(physical association)	0.500

BioGRID (51): LRCH4 (Affinity Capture-MS), KRT40 (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-8 (Two-hybrid), NOTCH2NL (Two-hybrid), RTN4 (Two-hybrid), MDFI (Two-hybrid), LRCH4 (Affinity Capture-MS), LRCH4 (Affinity Capture-MS), LRCH4 (Two-hybrid), LRCH4 (Proximity Label-MS), LRCH4 (Proximity Label-MS), LRCH4 (Affinity Capture-MS), LRCH4 (Affinity Capture-MS), LRCH4 (Two-hybrid)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: O75427, P26932, P41737, P52735, P62046, Q3UMG5, Q5S006, Q5VUJ6, Q60992, Q6Z8P4, Q8BVU0, Q921G6, Q96II8, Q9R0C8, Q9Y2L9, B9EUM5, B9G8P1, O14188, P14318, P15498, P19966, P27870, P31232, P37397, P37802, P37803, P37804, P37805, P51911, P54100, Q01995, Q08091, Q08092, Q08093, Q08094, Q08290, Q08DN7, Q14155, Q15052, Q15417

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	112
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
563415	GRCh37/hg19 7q22.1(chr7:98847725-102472176)x1	Pathogenic

SpliceAI

2192 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100575715:C:CA	donor_gain	1.0000
7:100575745:T:A	donor_gain	1.0000
7:100575778:TTTGG:T	acceptor_gain	1.0000
7:100575779:TTGG:T	acceptor_gain	1.0000
7:100575780:TGG:T	acceptor_gain	1.0000
7:100575781:GG:G	acceptor_gain	1.0000
7:100575783:C:CC	acceptor_gain	1.0000
7:100575783:C:CG	acceptor_loss	1.0000
7:100575784:T:A	acceptor_loss	1.0000
7:100575788:G:C	acceptor_gain	1.0000
7:100575788:G:GC	acceptor_gain	1.0000
7:100575792:G:C	acceptor_gain	1.0000
7:100575792:G:GC	acceptor_gain	1.0000
7:100575867:TGACC:T	donor_loss	1.0000
7:100575868:GAC:G	donor_loss	1.0000
7:100575869:A:AC	donor_gain	1.0000
7:100575869:A:AT	donor_loss	1.0000
7:100575870:C:CC	donor_gain	1.0000
7:100575870:CCA:C	donor_gain	1.0000
7:100575918:G:C	donor_gain	1.0000
7:100576009:C:CA	acceptor_loss	1.0000
7:100576013:C:CT	acceptor_gain	1.0000
7:100576014:A:T	acceptor_gain	1.0000
7:100576015:G:C	acceptor_gain	1.0000
7:100576015:G:GC	acceptor_gain	1.0000
7:100576017:G:C	acceptor_gain	1.0000
7:100576017:G:GC	acceptor_gain	1.0000
7:100576023:CACA:C	acceptor_gain	1.0000
7:100576026:A:C	acceptor_gain	1.0000
7:100576233:CTCA:C	donor_loss	1.0000

AlphaMissense

4309 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100582324:A:G	L119P	1.000
7:100582377:A:C	N101K	1.000
7:100582377:A:T	N101K	1.000
7:100578660:G:T	P242Q	0.999
7:100578674:G:C	N237K	0.999
7:100578674:G:T	N237K	0.999
7:100578743:G:C	N214K	0.999
7:100578743:G:T	N214K	0.999
7:100578759:A:G	L209P	0.999
7:100581809:A:T	V189D	0.999
7:100581815:A:G	L187P	0.999
7:100581868:G:C	N169K	0.999
7:100581868:G:T	N169K	0.999
7:100582042:A:G	L164P	0.999
7:100582042:A:T	L164H	0.999
7:100582095:G:C	N146K	0.999
7:100582095:G:T	N146K	0.999
7:100582096:T:A	N146I	0.999
7:100582097:T:A	N146Y	0.999
7:100582111:A:G	L141P	0.999
7:100582111:A:T	L141H	0.999
7:100582161:G:C	N124K	0.999
7:100582161:G:T	N124K	0.999
7:100582162:T:A	N124I	0.999
7:100582163:T:C	N124D	0.999
7:100582324:A:T	L119H	0.999
7:100582333:A:T	L116H	0.999
7:100582378:T:A	N101I	0.999
7:100582393:A:G	L96P	0.999
7:100582441:A:G	F80S	0.999

dbSNP variants (sampled 300 via entrez): RS1000004142 (7:100579437 A>G), RS1000083112 (7:100587590 A>C,G), RS1000116950 (7:100574325 T>C), RS1000446188 (7:100574090 T>C), RS1000870684 (7:100584604 G>T), RS1001011367 (7:100580828 G>C,T), RS1001051589 (7:100574981 G>A,T), RS1001232852 (7:100580694 TAAAC>T), RS1001403486 (7:100585632 TAAAGAGAA>T), RS1001627956 (7:100575808 T>C), RS1001743966 (7:100575558 C>T), RS1002248734 (7:100584752 G>C), RS1002870647 (7:100586993 G>A,C), RS1002969267 (7:100583314 C>T), RS1003306602 (7:100582963 A>T)

Disease associations

OMIM: gene MIM:620165 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006976_69	Macular thickness	6.000000e-10
GCST010702_48	Subcortical volume (MOSTest)	6.000000e-10
GCST010703_289	Brain morphology (MOSTest)	6.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Arsenic	increases expression, affects methylation, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
lipopolysaccharide, Escherichia coli O111 B4	increases expression, increases reaction	1
abrine	increases expression	1
Pam(3)CSK(4) peptide	increases expression, increases reaction	1
eprenetapopt	affects expression, affects reaction	1
Decitabine	increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Caffeine	affects phosphorylation	1
Camptothecin	decreases response to substance	1
Carmustine	decreases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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