LRRTM1

Summary

LRRTM1 (leucine rich repeat transmembrane neuronal 1, HGNC:19408) is a protein-coding gene on chromosome 2p12, encoding Leucine-rich repeat transmembrane neuronal protein 1 (Q86UE6). Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation, acting at both pre- and postsynaptic level.

Predicted to be involved in regulation of postsynaptic density assembly and regulation of presynapse assembly. Predicted to act upstream of or within several processes, including long-term synaptic potentiation; negative regulation of receptor internalization; and positive regulation of synapse assembly. Located in endoplasmic reticulum and growth cone. Is active in GABA-ergic synapse and postsynaptic specialization membrane.

Source: NCBI Gene 347730 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 2 total — 1 pathogenic
• MANE Select transcript: NM_178839

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19408
Approved symbol	LRRTM1
Name	leucine rich repeat transmembrane neuronal 1
Location	2p12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32082
Ensembl gene	ENSG00000162951
Ensembl biotype	protein_coding
OMIM	610867
Entrez	347730

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 nonsense_mediated_decay

ENST00000295057, ENST00000409148, ENST00000415098, ENST00000416268, ENST00000417012, ENST00000433224, ENST00000452811, ENST00000873881, ENST00000873882

RefSeq mRNA: 1 — MANE Select: NM_178839 NM_178839

CCDS: CCDS1966

Canonical transcript exons

ENST00000295057 — 2 exons

Exon	Start	End
ENSE00001070130	80304152	80304752
ENSE00001516782	80301878	80303878

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 90.56.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9682 / max 45.6647, expressed in 199 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29338	0.7161	167
29335	0.0949	62
29337	0.0701	47
29336	0.0594	38
29334	0.0277	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	90.56	gold quality
prefrontal cortex	UBERON:0000451	85.61	gold quality
nucleus accumbens	UBERON:0001882	85.33	gold quality
caudate nucleus	UBERON:0001873	84.38	gold quality
middle temporal gyrus	UBERON:0002771	84.01	gold quality
putamen	UBERON:0001874	83.26	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.49	gold quality
cortical plate	UBERON:0005343	82.45	gold quality
frontal cortex	UBERON:0001870	82.01	gold quality
frontal lobe	UBERON:0016525	82.00	gold quality
anterior cingulate cortex	UBERON:0009835	81.86	gold quality
right frontal lobe	UBERON:0002810	81.78	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.60	gold quality
neocortex	UBERON:0001950	81.41	gold quality
cerebral cortex	UBERON:0000956	80.37	gold quality
Ammon’s horn	UBERON:0001954	79.55	gold quality
primary visual cortex	UBERON:0002436	78.68	gold quality
entorhinal cortex	UBERON:0002728	78.43	gold quality
forebrain	UBERON:0001890	78.09	gold quality
hypothalamus	UBERON:0001898	77.37	gold quality
temporal lobe	UBERON:0001871	76.79	gold quality
amygdala	UBERON:0001876	76.69	gold quality
pancreatic ductal cell	CL:0002079	75.60	silver quality
superior frontal gyrus	UBERON:0002661	75.39	gold quality
brain	UBERON:0000955	73.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	73.38	gold quality
occipital lobe	UBERON:0002021	73.30	gold quality
Brodmann (1909) area 23	UBERON:0013554	72.27	gold quality
postcentral gyrus	UBERON:0002581	71.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.41	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	348.76
E-GEOD-114530	yes	290.96
E-ANND-3	no	3.75

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting LRRTM1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362

Literature-anchored findings (GeneRIF, showing 10)

• LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. (PMID:17667961)
• Whether or not LRRTM1 on chromosome 2p12 is indeed the genetic basis of handedness is still unclear, although the controversy of the claim seems indisputable. (PMID:19125365)
• While we agree (and indeed first proposed) that the variation underlying psychosis is intrinsically related to the cerebral torque, which we take to be the anatomical basis of language, we are unconvinced by the data for LRRTM1. (PMID:19125366)
• Recent study in which the first putative genetic effect on human handedness was identified (the imprinted locus LRRTM1 on human chromosome 2). (PMID:19125367)
• Results strengthen the evidence for an association of imprinted alleles of LRRTM1 with schizophrenia. Weaker supportive evidence was also obtained for a possible association of LRTTM1 with human brain asymmetry. (PMID:19626025)
• 16 SNPs in 12 genes showed significant interaction at P < .05, 3 of which survived correction for multiple testing (P < .0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). (PMID:21041608)
• CTNNA1 and CTNNA2 contain alternative 5’ exons linked to bidirectional promoters that are shared with the antisense oriented LRRTM2 and LRRTM1 genes, respectively. (PMID:21708131)
• Continuity between schizophrenia and schizotypy exists with regard to the psychological effects of allelic variation in LRRTM1, and epigenetic variation in the imprinted gene mediates the development and expression of human handedness. (PMID:24785688)
• Hypomethylation of the paternally inherited LRRTM1 promoter is linked to schizophrenia. (PMID:25111784)
• Functional cerebral asymmetries in the language domain are associated with the rs6733871 LRRTM1 polymorphism during cognitive control and top-down attention mechanisms. (PMID:28321770)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrtm1	ENSDARG00000052713
mus_musculus	Lrrtm1	ENSMUSG00000060780
rattus_norvegicus	LRRTM1	ENSRNOG00000006093

Paralogs (22): DCN (ENSG00000011465), RTN4R (ENSG00000040608), ASPN (ENSG00000106819), FLRT3 (ENSG00000125848), FLRT1 (ENSG00000126500), LRRC4 (ENSG00000128594), LRRC4B (ENSG00000131409), PODNL1 (ENSG00000132000), LRTM1 (ENSG00000144771), LRRC4C (ENSG00000148948), LRRC15 (ENSG00000172061), PODN (ENSG00000174348), LRRTM4 (ENSG00000176204), BGN (ENSG00000182492), LRRC19 (ENSG00000184434), FLRT2 (ENSG00000185070), GP1BA (ENSG00000185245), RTN4RL1 (ENSG00000185924), RTN4RL2 (ENSG00000186907), NYX (ENSG00000188937), LRRC66 (ENSG00000188993), LRRTM3 (ENSG00000198739)

Protein

Protein identifiers

Leucine-rich repeat transmembrane neuronal protein 1 — Q86UE6 (reviewed: Q86UE6)

All UniProt accessions (4): C9JEE2, C9JF97, C9JPM9, Q86UE6

UniProt curated annotations — full annotation on UniProt →

Function. Exhibits strong synaptogenic activity, restricted to excitatory presynaptic differentiation, acting at both pre- and postsynaptic level.

Subcellular location. Cell membrane. Postsynaptic cell membrane.

Tissue specificity. Predominantly expressed in forebrain regions including thalamus and cerebral cortex.

Miscellaneous. This gene is imprinted, being predominantly expressed from the paternal allele and showing a variable pattern of maternal down-regulation. May be associated paternally with handedness and schizophrenia.

Similarity. Belongs to the LRRTM family.

RefSeq proteins (1): NP_849161* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF13855

UniProt features (24 total): repeat 10, glycosylation site 4, domain 2, topological domain 2, signal peptide 1, chain 1, region of interest 1, sequence variant 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UE6-F1	79.41	0.57

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 (4): 56, 63, 130, 380

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: 166 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_BEHAVIOR, GOBP_SYNAPSE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, LHX3_01, CHX10_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, CAGCTG_AP4_Q5, FOXD3_01

GO Biological Process (9): negative regulation of receptor internalization (GO:0002091), locomotory behavior (GO:0007626), receptor internalization (GO:0031623), protein localization to synapse (GO:0035418), exploration behavior (GO:0035640), synapse organization (GO:0050808), establishment of localization in cell (GO:0051649), positive regulation of synapse assembly (GO:0051965), long-term synaptic potentiation (GO:0060291)

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

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), axon (GO:0030424), growth cone (GO:0030426), GABA-ergic synapse (GO:0098982), postsynaptic specialization membrane (GO:0099634), 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
behavior	2
synaptic membrane	2
regulation of receptor internalization	1
receptor internalization	1
negative regulation of receptor-mediated endocytosis	1
receptor-mediated endocytosis	1
protein localization to cell junction	1
cell junction organization	1
establishment of localization	1
cellular localization	1
synapse assembly	1
positive regulation of nervous system development	1
regulation of synapse assembly	1
positive regulation of cell junction assembly	1
regulation of synaptic plasticity	1
positive regulation of synaptic transmission	1
molecular transducer activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
neuron projection	1
site of polarized growth	1
distal axon	1
synapse	1
postsynaptic membrane	1
postsynaptic specialization	1
cellular anatomical structure	1
cell junction	1
postsynapse	1

Protein interactions and networks

STRING

2290 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRTM1	CTNNA2	P26232	881
LRRTM1	TRAPPC10	P48553	865
LRRTM1	NRXN1	Q9ULB1	749
LRRTM1	NRXN2	Q9P2S2	746
LRRTM1	NLGN1	Q8N2Q7	668
LRRTM1	DLG4	P78352	653
LRRTM1	NLGN2	Q8NFZ4	598
LRRTM1	CLSTN3	Q9BQT9	595
LRRTM1	NEFL	P07196	587
LRRTM1	CBLN1	P02682	568
LRRTM1	GRIK2	Q13002	555
LRRTM1	NLGN3	Q9NZ94	542
LRRTM1	MAP1B	P46821	506
LRRTM1	PCSK6	P29122	500
LRRTM1	CNPY2	Q9Y2B0	497

IntAct

5 interactions, top by confidence:

A	B	Type	Score
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
	LRRTM1	psi-mi:“MI:0915”(physical association)	0.370
LRRTM1	TMEM223	psi-mi:“MI:0914”(association)	0.350
LRRTM1	AGRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (76): LRRTM1 (Synthetic Lethality), AREL1 (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), SMPD2 (Affinity Capture-MS), CNPY3 (Affinity Capture-MS), AMIGO1 (Affinity Capture-MS), MARC1 (Affinity Capture-MS), RAB12 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS), TYW1 (Affinity Capture-MS), NSUN3 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), PDE3B (Affinity Capture-MS), STIM1 (Affinity Capture-MS), PIGA (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2ARI4, A6NDA9, B0BLW3, B4F7C5, D3ZAL8, D3ZTV3, D4A6D8, D4A7P2, E7FE13, F1MT22, O14498, O43155, O43300, P0DM44, P83286, Q149C3, Q5NVQ6, Q5R6B1, Q5R7M3, Q5RAC4, Q6PFC5, Q6RKD8, Q80WD0, Q80XG9, Q80ZD7, Q80ZD8, Q80ZD9, Q810C0, Q810C1, Q86SJ2, Q86UE6, Q86UN2, Q86VH4, Q86VH5, Q86WK6, Q8BGA3, Q8BLU0, Q8BZ81, Q8C2S7

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, O94813, Q13641, Q3URE9, Q5R7M3, Q6UXM1, Q6ZSA7, Q7TNJ4, Q80ZD5, Q80ZD9, Q86SJ2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
442633	GRCh37/hg19 2p13.1-11.2(chr2:74365484-89129064)x1	Pathogenic

SpliceAI

673 predictions. Top by Δscore:

Variant	Effect	Δscore
2:80302408:T:TA	acceptor_gain	0.9800
2:80302415:T:A	acceptor_gain	0.9500
2:80302417:C:CA	acceptor_gain	0.9400
2:80304170:A:AT	donor_gain	0.9100
2:80304188:C:CA	donor_gain	0.9100
2:80304748:GTGTC:G	donor_gain	0.9100
2:80303898:G:T	acceptor_gain	0.9000
2:80304150:AC:A	donor_gain	0.8700
2:80304151:CC:C	donor_gain	0.8700
2:80303897:C:CT	acceptor_gain	0.8600
2:80304399:T:TA	donor_gain	0.8300
2:80304169:C:CT	donor_gain	0.8200
2:80303872:C:A	donor_gain	0.8100
2:80304174:T:TA	donor_gain	0.8100
2:80292136:GC:G	donor_gain	0.8000
2:80304410:T:TA	donor_gain	0.8000
2:80292137:C:G	donor_gain	0.7900
2:80304147:CCCA:C	donor_gain	0.7900
2:80301740:A:G	acceptor_gain	0.7800
2:80302420:T:A	acceptor_gain	0.7800
2:80302422:C:CA	acceptor_gain	0.7800
2:80302738:TGG:T	donor_gain	0.7800
2:80304294:A:AC	donor_gain	0.7800
2:80304295:C:CC	donor_gain	0.7800
2:80304528:G:T	donor_gain	0.7700
2:80304536:C:CT	donor_gain	0.7700
2:80292292:A:AG	acceptor_gain	0.7600
2:80292293:G:GG	acceptor_gain	0.7600
2:80302761:G:GT	donor_gain	0.7400
2:80302824:G:GT	donor_gain	0.7400

AlphaMissense

3413 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:80303179:A:G	L214P	1.000
2:80302794:G:C	C342W	0.999
2:80302795:C:G	C342S	0.999
2:80302796:A:G	C342R	0.999
2:80302796:A:T	C342S	0.999
2:80302866:G:C	C318W	0.999
2:80302867:C:T	C318Y	0.999
2:80302868:A:G	C318R	0.999
2:80302872:C:A	W316C	0.999
2:80302872:C:G	W316C	0.999
2:80302874:A:G	W316R	0.999
2:80302874:A:T	W316R	0.999
2:80302878:G:C	N314K	0.999
2:80302878:G:T	N314K	0.999
2:80302950:G:C	N290K	0.999
2:80302950:G:T	N290K	0.999
2:80302966:A:G	L285P	0.999
2:80303022:G:C	N266K	0.999
2:80303022:G:T	N266K	0.999
2:80303163:G:C	N219K	0.999
2:80303163:G:T	N219K	0.999
2:80303173:A:G	L216P	0.999
2:80303188:A:T	L211H	0.999
2:80303251:A:G	L190P	0.999
2:80303268:G:C	C184W	0.999
2:80303278:A:G	F181S	0.999
2:80303323:A:G	L166P	0.999
2:80303332:A:T	L163H	0.999
2:80303379:G:C	N147K	0.999
2:80303379:G:T	N147K	0.999

dbSNP variants (sampled 300 via entrez): RS1000644989 (2:80290318 A>G,T), RS1000858571 (2:80296104 G>A,C,T), RS1001171219 (2:80300307 T>G), RS1001641782 (2:80300104 G>T), RS1001869933 (2:80289583 G>A), RS1001985415 (2:80301505 G>A), RS1002832111 (2:80292674 G>A), RS1002845111 (2:80299073 G>A), RS1002902617 (2:80306329 A>T), RS1002974987 (2:80305962 G>C,T), RS1003203761 (2:80299306 T>G), RS1003249673 (2:80288306 G>A,C), RS1003541382 (2:80288232 G>T), RS1003644944 (2:80294263 G>T), RS1003719076 (2:80305571 T>A)

Disease associations

OMIM: gene MIM:610867 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST007327_163	Smoking status (ever vs never smokers)	9.000000e-11
GCST009391_11	Metabolite levels	4.000000e-06
GCST009391_515	Metabolite levels	1.000000e-06
GCST009391_667	Metabolite levels	3.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior
EFO:0007813	cotinine measurement
EFO:0010117	pyruvate measurement
EFO:0009770	leucine measurement

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
trichostatin A	increases expression	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression, decreases expression	2
Panobinostat	increases reaction, affects cotreatment, increases expression, affects expression	2
Valproic Acid	affects expression, increases expression	2
arsenite	increases methylation	1
sodium arsenite	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	affects expression, increases reaction	1
Carbamazepine	affects expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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