LRRTM3

Summary

LRRTM3 (leucine rich repeat transmembrane neuronal 3, HGNC:19410) is a protein-coding gene on chromosome 10q21.3, encoding Leucine-rich repeat transmembrane neuronal protein 3 (Q86VH5). Exhibits a limited synaptogenic activity in vitro, restricted to excitatory presynaptic differentiation.

Involved in regulation of presynapse assembly. Acts upstream of or within positive regulation of amyloid-beta formation. Is active in glutamatergic synapse.

Source: NCBI Gene 347731 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_178011

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19410
Approved symbol	LRRTM3
Name	leucine rich repeat transmembrane neuronal 3
Location	10q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198739
Ensembl biotype	protein_coding
OMIM	610869
Entrez	347731

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000361320, ENST00000472278, ENST00000485868

RefSeq mRNA: 1 — MANE Select: NM_178011 NM_178011

CCDS: CCDS7270

Canonical transcript exons

ENST00000361320 — 3 exons

Exon	Start	End
ENSE00001217131	66926921	66928452
ENSE00001369572	66926036	66926587
ENSE00001461384	67097587	67101551

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 98.41.

FANTOM5 (CAGE): breadth broad, TPM avg 4.7531 / max 449.1854, expressed in 255 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105203	2.5233	208
105204	2.1753	202
105205	0.0545	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	98.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.04	gold quality
superior frontal gyrus	UBERON:0002661	86.17	gold quality
left testis	UBERON:0004533	84.73	gold quality
ventricular zone	UBERON:0003053	84.17	gold quality
prefrontal cortex	UBERON:0000451	84.13	gold quality
testis	UBERON:0000473	84.12	gold quality
right testis	UBERON:0004534	83.64	gold quality
frontal cortex	UBERON:0001870	80.59	gold quality
primary visual cortex	UBERON:0002436	79.52	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.24	gold quality
cortical plate	UBERON:0005343	77.89	gold quality
cerebral cortex	UBERON:0000956	77.75	gold quality
ganglionic eminence	UBERON:0004023	77.11	gold quality
islet of Langerhans	UBERON:0000006	76.82	gold quality
nucleus accumbens	UBERON:0001882	75.98	gold quality
brain	UBERON:0000955	75.05	gold quality
right frontal lobe	UBERON:0002810	74.83	gold quality
anterior cingulate cortex	UBERON:0009835	74.83	gold quality
putamen	UBERON:0001874	73.95	gold quality
caudate nucleus	UBERON:0001873	73.73	gold quality
adrenal tissue	UBERON:0018303	73.55	gold quality
cerebellum	UBERON:0002037	72.98	gold quality
cerebellar cortex	UBERON:0002129	72.89	gold quality
cerebellar hemisphere	UBERON:0002245	72.80	gold quality
temporal lobe	UBERON:0001871	72.33	gold quality
adenohypophysis	UBERON:0002196	72.22	gold quality
amygdala	UBERON:0001876	72.18	gold quality
hypothalamus	UBERON:0001898	72.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ENAD-27	yes	10.26
E-ANND-3	yes	3.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

245 targeting LRRTM3, 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-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 7)

• Data suggest that LRRTM3 is a functional and positional candidate gene for Alzheimer disease, and, given its receptor-like structure and restricted expression, a potential therapeutic target. (PMID:17098871)
• An ancestral risk haplotype clade in ACE and putative multilocus association between ACE, A2M, and LRRTM3 in Alzheimer disease. (PMID:19105203)
• Apart from the complexity of its regulation, alterations in both CTNNA3 and LRTMM3 are implicated in human disease. (PMID:21598020)
• One single-nucleotide polymorphism in the promoter region and a block of 4 single-nucleotide polymorphisms in intron 2 were associated with AD in the National Institute on Aging Late-Onset Alzheimer’s Disease data set or the Caribbean Hispanic data set. (PMID:22393166)
• LRRTM3 is not an essential regulator of amyloid-beta production in adult mice; there are no differences in genotype between levels of Abeta or Abeta protein precursor C-terminal fragments in vivo. (PMID:22710909)
• protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD (PMID:23750206)
• LRRTM3 polymorphisms may play a role in the pathogenesis of late-onset Alzheimer’s disease (LOAD) in a Northern Han Chinese population. (PMID:24463050)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Lrrtm3	ENSMUSG00000042846
rattus_norvegicus	Lrrtm3	ENSRNOG00000026466

Paralogs (22): DCN (ENSG00000011465), RTN4R (ENSG00000040608), ASPN (ENSG00000106819), FLRT3 (ENSG00000125848), FLRT1 (ENSG00000126500), LRRC4 (ENSG00000128594), LRRC4B (ENSG00000131409), PODNL1 (ENSG00000132000), LRTM1 (ENSG00000144771), LRRC4C (ENSG00000148948), LRRTM1 (ENSG00000162951), LRRC15 (ENSG00000172061), PODN (ENSG00000174348), LRRTM4 (ENSG00000176204), BGN (ENSG00000182492), LRRC19 (ENSG00000184434), FLRT2 (ENSG00000185070), GP1BA (ENSG00000185245), RTN4RL1 (ENSG00000185924), RTN4RL2 (ENSG00000186907), NYX (ENSG00000188937), LRRC66 (ENSG00000188993)

Protein

Protein identifiers

Leucine-rich repeat transmembrane neuronal protein 3 — Q86VH5 (reviewed: Q86VH5)

All UniProt accessions (1): Q86VH5

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits a limited synaptogenic activity in vitro, restricted to excitatory presynaptic differentiation. May play a role in the development and maintenance of the vertebrate nervous system.

Subcellular location. Cell membrane. Postsynaptic cell membrane.

Tissue specificity. Expressed in neuronal tissues.

Similarity. Belongs to the LRRTM family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86VH5-1	1	yes
Q86VH5-2	2

RefSeq proteins (1): NP_821079* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR050541	LRR_TM_domain-containing	Family

Pfam: PF00560, PF13855

UniProt features (23 total): repeat 10, domain 2, glycosylation site 2, topological domain 2, splice variant 2, signal peptide 1, chain 1, region of interest 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86VH5-F1	74.23	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 126, 357

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 221 (showing top): HNF3ALPHA_Q6, GOBP_SYNAPSE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, chr10q21, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, FOXO4_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, CAGCTG_AP4_Q5, CEBPB_01, FOXD3_01

GO Biological Process (3): positive regulation of synapse assembly (GO:0051965), positive regulation of amyloid-beta formation (GO:1902004), regulation of presynapse assembly (GO:1905606)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (6): plasma membrane (GO:0005886), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synapse (GO:0045202), postsynaptic membrane (GO:0045211)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of synapse assembly	2
synapse assembly	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
amyloid-beta formation	1
regulation of amyloid-beta formation	1
positive regulation of amyloid precursor protein catabolic process	1
presynapse assembly	1
regulation of presynapse organization	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1
synapse	1
cellular anatomical structure	1
cell junction	1
synaptic membrane	1
postsynapse	1

Protein interactions and networks

STRING

1870 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRTM3	CTNNA3	Q9UI47	891
LRRTM3	B3GNT3	Q9Y2A9	877
LRRTM3	NRXN2	Q9P2S2	779
LRRTM3	GPC1	P35052	733
LRRTM3	NRXN1	Q9ULB1	701
LRRTM3	BACE1	P56817	659
LRRTM3	PTPRS	Q13332	638
LRRTM3	APP	P05067	503
LRRTM3	CNTNAP1	P78357	495
LRRTM3	SCN1A	P35498	478
LRRTM3	NXPH1	P58417	458
LRRTM3	GPC4	O75487	447
LRRTM3	DLK1	P15803	422
LRRTM3	CTNNA2	P26232	419
LRRTM3	NLGN2	Q8NFZ4	414
LRRTM3	NLGN1	Q8N2Q7	414

IntAct

6 interactions, top by confidence:

A	B	Type	Score
LRRTM4	AP3B1	psi-mi:“MI:0914”(association)	0.530
LRRTM3	SGPL1	psi-mi:“MI:0914”(association)	0.530
LRRTM3	ADCY9	psi-mi:“MI:0914”(association)	0.350
LRRTM3	GAPDHS	psi-mi:“MI:0914”(association)	0.350
LRRTM3	URB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (19): LRRTM3 (Affinity Capture-RNA), LRRTM3 (Affinity Capture-MS), GPC1 (Affinity Capture-MS), CEBPZ (Affinity Capture-MS), HIST1H1A (Affinity Capture-MS), ADCY9 (Affinity Capture-MS), GPC3 (Affinity Capture-MS), NRXN3 (Affinity Capture-MS), TMED8 (Affinity Capture-MS), GPC6 (Affinity Capture-MS), PCYOX1 (Affinity Capture-MS), CNPY4 (Affinity Capture-MS), GPC4 (Affinity Capture-MS), CNPY3 (Affinity Capture-MS), TGFBR3 (Affinity Capture-MS)

ESM2 similar proteins: A0N0X6, A4IIW9, B0BLW3, B1H134, B1H234, B4F7C5, D3ZAL8, D3ZTV3, D4A7P2, E5DHB5, F1NUK7, F7D3V9, O43155, O43300, O94898, P58681, Q32Q07, Q3SXY7, Q3URE9, Q504C1, Q50L44, Q52KR2, Q5R482, Q5R6T0, Q5RDJ4, Q61809, Q66HV9, Q6RKD8, Q6UXK5, Q70AK3, Q7L985, Q80XG9, Q80ZD7, Q80ZD8, Q80ZD9, Q86VH4, Q86VH5, Q8BGA3, Q8BGT1, Q8BLU0

Diamond homologs: A1A4H9, B4F7C5, D3ZAL8, D4A6D8, D4A7P2, O43300, O75093, P58874, Q5R6B1, Q80XG9, Q86UE6, Q86VH4, Q86VH5, Q8BGA3, Q8BZ81, Q8C2S7, Q8K377, Q920A0, Q9BGP6, Q9UBM4, O88279, P70186, Q1ENI8, Q3ZBN5, Q80TR4, Q99MQ4, Q9BXN1, O02678, Q80ZD7, Q80ZD8, A4IGL7, G5EFX6, O15335, O46377, O46378, O46379, O46390, O46403, O46542, O75094

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

2297 predictions. Top by Δscore:

Variant	Effect	Δscore
10:66981897:C:CT	acceptor_gain	1.0000
10:67050098:T:TA	donor_gain	1.0000
10:67050102:T:TA	donor_gain	1.0000
10:67012747:CACTT:C	acceptor_gain	0.9900
10:67037303:T:G	acceptor_gain	0.9900
10:67088289:GAA:G	donor_gain	0.9900
10:67097581:CCCCA:C	acceptor_loss	0.9900
10:67097582:CCCA:C	acceptor_loss	0.9900
10:67097583:CCA:C	acceptor_loss	0.9900
10:67097584:CA:C	acceptor_loss	0.9900
10:67097585:A:AG	acceptor_gain	0.9900
10:67097586:G:GG	acceptor_gain	0.9900
10:66970392:A:G	donor_gain	0.9800
10:66981898:A:T	acceptor_gain	0.9800
10:67012749:CTT:C	acceptor_gain	0.9800
10:67012752:C:CC	acceptor_gain	0.9800
10:67049975:T:C	donor_gain	0.9800
10:67082031:TAGGC:T	donor_gain	0.9800
10:66957242:AGAT:A	donor_gain	0.9700
10:66957243:GATG:G	donor_gain	0.9700
10:66981891:T:C	acceptor_gain	0.9700
10:66981891:T:TC	acceptor_gain	0.9700
10:66989845:ATCT:A	acceptor_gain	0.9700
10:66989846:TCTC:T	acceptor_gain	0.9700
10:67050138:A:C	donor_gain	0.9700
10:66926583:GA:G	donor_gain	0.9600
10:67050103:C:A	donor_gain	0.9600
10:67097586:GAT:G	acceptor_gain	0.9600
10:67097586:GATA:G	acceptor_gain	0.9600
10:66989848:T:TG	acceptor_gain	0.9500

AlphaMissense

3824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:66927028:T:C	C38R	1.000
10:66927055:T:A	C47S	1.000
10:66927055:T:C	C47R	1.000
10:66927056:G:A	C47Y	1.000
10:66927056:G:C	C47S	1.000
10:66927057:T:G	C47W	1.000
10:66927113:T:C	L66S	1.000
10:66927115:T:C	S67P	1.000
10:66927119:T:C	L68P	1.000
10:66927122:G:C	R69P	1.000
10:66927129:C:A	N71K	1.000
10:66927129:C:G	N71K	1.000
10:66927158:T:C	F81S	1.000
10:66927176:T:A	L87H	1.000
10:66927176:T:C	L87P	1.000
10:66927183:G:C	W89C	1.000
10:66927183:G:T	W89C	1.000
10:66927185:T:C	L90P	1.000
10:66927191:T:A	L92H	1.000
10:66927191:T:C	L92P	1.000
10:66927194:A:T	D93V	1.000
10:66927197:A:C	H94P	1.000
10:66927199:A:T	N95Y	1.000
10:66927200:A:T	N95I	1.000
10:66927201:C:A	N95K	1.000
10:66927201:C:G	N95K	1.000
10:66927230:T:C	F105S	1.000
10:66927248:T:A	L111H	1.000
10:66927248:T:C	L111P	1.000
10:66927257:T:A	L114Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000041377 (10:67077860 TAAAG>T), RS1000049278 (10:67099054 C>A,G,T), RS1000052119 (10:66952938 G>A,T), RS1000076433 (10:67073394 T>A,G), RS1000078165 (10:67015662 A>G), RS1000127184 (10:66940054 A>C), RS1000143286 (10:67017081 C>A), RS1000147524 (10:67082062 C>A), RS1000162284 (10:66934490 C>A), RS1000163210 (10:66990651 G>C), RS1000170137 (10:67018609 C>G,T), RS1000179445 (10:67060338 C>A), RS1000183930 (10:67033630 C>T), RS1000207266 (10:66993486 G>A), RS1000220442 (10:66966429 A>T)

Disease associations

OMIM: gene MIM:610869 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

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)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10997459	CTNNA3, LRRTM3		0.00	0

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation	2
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression, affects response to substance	1
Methapyrilene	increases methylation	1
Phenobarbital	decreases expression	1
Silicon Dioxide	decreases expression	1
Triclosan	decreases expression	1
Asbestos, Crocidolite	affects methylation	1

Clinical trials (associated diseases)

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