ISLR2

Summary

ISLR2 (immunoglobulin superfamily containing leucine rich repeat 2, HGNC:29286) is a protein-coding gene on chromosome 15q24.1, encoding Immunoglobulin superfamily containing leucine-rich repeat protein 2 (Q6UXK2). Required for axon extension during neural development.

Predicted to be involved in positive regulation of axon extension. Predicted to be located in plasma membrane. Predicted to be active in cell surface.

Source: NCBI Gene 57611 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies/dysmorphic syndrome (Moderate, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 88 total — 1 likely-pathogenic
• MANE Select transcript: NM_020851

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29286
Approved symbol	ISLR2
Name	immunoglobulin superfamily containing leucine rich repeat 2
Location	15q24.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1465
Ensembl gene	ENSG00000167178
Ensembl biotype	protein_coding
OMIM	614179
Entrez	57611

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000361742, ENST00000435464, ENST00000453268, ENST00000561740, ENST00000561975, ENST00000565068, ENST00000565159, ENST00000565332, ENST00000565540, ENST00000567206, ENST00000569886, ENST00000938681, ENST00000960910, ENST00000960911

RefSeq mRNA: 4 — MANE Select: NM_020851 NM_001130136, NM_001130137, NM_001130138, NM_020851

CCDS: CCDS10259

Canonical transcript exons

ENST00000453268 — 3 exons

Exon	Start	End
ENSE00001685290	74131207	74131316
ENSE00001685876	74130586	74130621
ENSE00001873119	74132747	74136802

Expression profiles

Bgee: expression breadth ubiquitous, 154 present calls, max score 99.35.

FANTOM5 (CAGE): breadth broad, TPM avg 2.4397 / max 380.6400, expressed in 281 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147651	0.8999	101
147642	0.5738	194
147647	0.2623	71
147643	0.2094	79
147644	0.1195	51
147646	0.0835	34
147650	0.0806	31
147645	0.0773	30
147649	0.0573	25
147652	0.0443	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.35	gold quality
ganglionic eminence	UBERON:0004023	98.38	gold quality
ventricular zone	UBERON:0003053	84.24	gold quality
left testis	UBERON:0004533	83.02	gold quality
right testis	UBERON:0004534	82.56	gold quality
prefrontal cortex	UBERON:0000451	81.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.71	gold quality
testis	UBERON:0000473	79.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.95	gold quality
anterior cingulate cortex	UBERON:0009835	77.58	gold quality
apex of heart	UBERON:0002098	76.75	gold quality
right frontal lobe	UBERON:0002810	76.72	gold quality
nucleus accumbens	UBERON:0001882	76.52	gold quality
caudate nucleus	UBERON:0001873	75.03	gold quality
putamen	UBERON:0001874	75.02	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	74.99	gold quality
neocortex	UBERON:0001950	74.64	gold quality
frontal cortex	UBERON:0001870	73.95	gold quality
pancreatic ductal cell	CL:0002079	72.51	silver quality
cerebral cortex	UBERON:0000956	70.24	gold quality
heart left ventricle	UBERON:0002084	68.02	gold quality
forebrain	UBERON:0001890	67.26	gold quality
cardiac ventricle	UBERON:0002082	67.10	gold quality
upper arm skin	UBERON:0004263	66.25	gold quality
hypothalamus	UBERON:0001898	65.83	gold quality
brain	UBERON:0000955	64.65	gold quality
hindlimb stylopod muscle	UBERON:0004252	64.59	gold quality
smooth muscle tissue	UBERON:0001135	64.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	63.83	gold quality
lower esophagus	UBERON:0013473	63.63	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	178.96
E-ANND-3	no	3.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting ISLR2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-7106-5P	99.53	67.47	3574

Literature-anchored findings (GeneRIF, showing 1)

• Deletion in ISLR2 gene is associated with autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension. (PMID:30483960)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Islr2	ENSMUSG00000051243
rattus_norvegicus	Islr2	ENSRNOG00000050714

Paralogs (3): LRRN4 (ENSG00000125872), ISLR (ENSG00000129009), LRRN4CL (ENSG00000177363)

Protein

Protein identifiers

Immunoglobulin superfamily containing leucine-rich repeat protein 2 — Q6UXK2 (reviewed: Q6UXK2)

Alternative names: Leucine-rich repeat domain and immunoglobulin domain-containing axon extension protein

All UniProt accessions (4): Q6UXK2, H3BM69, H3BM95, H3BNZ6

UniProt curated annotations — full annotation on UniProt →

Function. Required for axon extension during neural development.

Subunit / interactions. Homomultimer. Interacts with NTRK1/TrkA.

Subcellular location. Cell membrane.

RefSeq proteins (4): NP_001123608, NP_001123609, NP_001123610, NP_065902* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF13855

UniProt features (30 total): glycosylation site 6, repeat 5, domain 3, region of interest 3, compositionally biased region 3, modified residue 2, topological domain 2, signal peptide 1, chain 1, disulfide bond 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-Q6UXK2-F1	67.24	0.34

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 (2): 719, 720

Disulfide bonds (1): 260–355

Glycosylation sites (6): 52, 121, 337, 364, 474, 563

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MODULE_205, GOBP_POSITIVE_REGULATION_OF_CELL_GROWTH, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_AXON_EXTENSION, GOBP_REGULATION_OF_CELL_SIZE

GO Biological Process (2): nervous system development (GO:0007399), positive regulation of axon extension (GO:0045773)

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

GO Cellular Component (3): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
system development	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1097 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISLR2	GOLGA6A	Q9NYA3	507
ISLR2	UBL7	Q96S82	452
ISLR2	CCDC33	Q8N5R6	451
ISLR2	RNF26	Q9BY78	428
ISLR2	EPHA3	P29320	396
ISLR2	COL18A1	P39060	385
ISLR2	N4BP2	Q86UW6	384
ISLR2	TIE1	P35590	379
ISLR2	NTN3	O00634	373
ISLR2	BRINP2	Q9C0B6	370
ISLR2	SRRM3	A6NNA2	367
ISLR2	TBP	P20226	353
ISLR2	PI15	O43692	353
ISLR2	NID1	P14543	353
ISLR2	ENPEP	Q07075	353
ISLR2	ADAMTS16	Q8TE57	353
ISLR2	WIF1	Q9Y5W5	353
ISLR2	GPC2	Q8N158	353
ISLR2	CREB3	O43889	353

IntAct

45 interactions, top by confidence:

A	B	Type	Score
ISLR2	LEP	psi-mi:“MI:0915”(physical association)	0.590
ISLR2	LEP	psi-mi:“MI:0407”(direct interaction)	0.590
ISLR2	LEP	psi-mi:“MI:0403”(colocalization)	0.590
NKG7	ISLR2	psi-mi:“MI:0915”(physical association)	0.560
ISLR2	MRAP2	psi-mi:“MI:0915”(physical association)	0.560
EMP1	ISLR2	psi-mi:“MI:0915”(physical association)	0.560
UPK1B	ISLR2	psi-mi:“MI:0915”(physical association)	0.560
STRIT1	ISLR2	psi-mi:“MI:0915”(physical association)	0.560
ISLR2	LAPTM4B	psi-mi:“MI:0915”(physical association)	0.560
IL6R	ISLR2	psi-mi:“MI:0915”(physical association)	0.540
ISLR2	IL6R	psi-mi:“MI:0407”(direct interaction)	0.540
ISLR2	Lep	psi-mi:“MI:0407”(direct interaction)	0.440
ICAM5	ISLR2	psi-mi:“MI:0407”(direct interaction)	0.440
ISLR2	LTF	psi-mi:“MI:0407”(direct interaction)	0.440
ISLR2	IGFBPL1	psi-mi:“MI:0407”(direct interaction)	0.440
IGFBP7	ISLR2	psi-mi:“MI:0407”(direct interaction)	0.440
MPZ	ISLR2	psi-mi:“MI:0915”(physical association)	0.400
ISLR2	PIGR	psi-mi:“MI:0915”(physical association)	0.400
ISLR2	PRTG	psi-mi:“MI:0915”(physical association)	0.400
ISLR2		psi-mi:“MI:0915”(physical association)	0.370
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	CACNB4	psi-mi:“MI:0914”(association)	0.350

BioGRID (10): ISLR2 (Affinity Capture-MS), ISLR2 (Two-hybrid), ISLR2 (Two-hybrid), ISLR2 (Two-hybrid), ISLR2 (Two-hybrid), ISLR2 (Two-hybrid), LOC100507537 (Two-hybrid), ISLR2 (Affinity Capture-MS), ISLR2 (Affinity Capture-MS), ISLR2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

Diamond homologs: A2AJ76, A4IFA6, A6NJW4, A8WHP9, O14498, P14770, P59034, P59035, Q13641, Q15109, Q28173, Q4R8Y9, Q5NVQ6, Q5RKR3, Q62151, Q63495, Q6GU68, Q6UXK2, Q6WRH9, Q96RW7, A2AAJ9, A6H793, E7FE13, F1MLX5, P13224, P56400, Q58EX2, Q6UY18, Q6V4S5, Q9BY71, Q9JJM7, A2ARI4, O08852, P98161, Q2I0M4, Q504C1, Q9BXB1, Q91009, Q8C031, Q9HCJ2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	81
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4278451	NM_020851.3(ISLR2):c.968G>A (p.Trp323Ter)	Likely pathogenic

SpliceAI

810 predictions. Top by Δscore:

Variant	Effect	Δscore
15:74129726:GGGT:G	donor_gain	0.9900
15:74129727:G:GT	donor_gain	0.9900
15:74130085:G:GT	donor_gain	0.9900
15:74130085:GAA:G	donor_gain	0.9900
15:74130088:G:GG	donor_gain	0.9900
15:74130101:GCT:G	donor_gain	0.9900
15:74130620:GG:G	donor_gain	0.9900
15:74130621:GG:G	donor_gain	0.9900
15:74131201:CCACA:C	acceptor_loss	0.9900
15:74131202:CACAG:C	acceptor_loss	0.9900
15:74131203:ACAGC:A	acceptor_loss	0.9900
15:74131204:CA:C	acceptor_loss	0.9900
15:74131205:A:AC	acceptor_loss	0.9900
15:74131205:A:AG	acceptor_gain	0.9900
15:74131206:G:GG	acceptor_gain	0.9900
15:74131206:G:GT	acceptor_loss	0.9900
15:74131206:GC:G	acceptor_gain	0.9900
15:74131206:GCC:G	acceptor_gain	0.9900
15:74131206:GCCA:G	acceptor_gain	0.9900
15:74131206:GCCAC:G	acceptor_gain	0.9900
15:74131314:TGGG:T	donor_loss	0.9900
15:74131315:GG:G	donor_gain	0.9900
15:74131316:GG:G	donor_gain	0.9900
15:74131317:G:C	donor_loss	0.9900
15:74131317:G:GG	donor_gain	0.9900
15:74132728:ACCT:A	acceptor_gain	0.9900
15:74132731:T:TA	acceptor_gain	0.9900
15:74130110:GC:G	donor_gain	0.9800
15:74131204:C:G	acceptor_gain	0.9800
15:74132728:ACCTG:A	acceptor_gain	0.9800

AlphaMissense

4734 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:74132936:A:T	N61I	1.000
15:74132997:G:C	W81C	1.000
15:74132997:G:T	W81C	1.000
15:74133081:C:A	N109K	1.000
15:74133081:C:G	N109K	1.000
15:74132855:T:G	F34C	0.999
15:74132863:T:A	C37S	0.999
15:74132863:T:C	C37R	0.999
15:74132864:G:A	C37Y	0.999
15:74132864:G:C	C37S	0.999
15:74132865:C:G	C37W	0.999
15:74132921:T:C	L56P	0.999
15:74132927:T:C	L58P	0.999
15:74132935:A:T	N61Y	0.999
15:74132937:C:A	N61K	0.999
15:74132937:C:G	N61K	0.999
15:74132966:T:G	F71C	0.999
15:74132989:T:C	S79P	0.999
15:74132993:T:C	L80P	0.999
15:74132995:T:A	W81R	0.999
15:74132995:T:C	W81R	0.999
15:74132999:T:C	L82P	0.999
15:74133056:T:A	L101H	0.999
15:74133065:T:C	L104P	0.999
15:74133068:A:G	D105G	0.999
15:74133071:T:C	L106P	0.999
15:74133074:G:T	S107I	0.999
15:74133134:T:C	L127P	0.999
15:74133137:T:A	L128H	0.999
15:74133137:T:C	L128P	0.999

dbSNP variants (sampled 300 via entrez): RS1000021785 (15:74140679 A>G), RS1000027460 (15:74135936 G>C), RS1000028981 (15:74136896 C>T), RS1000215185 (15:74109956 G>A), RS1000219885 (15:74140916 T>A), RS1000312424 (15:74102598 A>G), RS1000338705 (15:74102961 T>C,G), RS1000394964 (15:74128440 G>A,T), RS1000584027 (15:74108990 G>T), RS1000633208 (15:74135605 G>T), RS1000644023 (15:74099038 G>C), RS1000676554 (15:74099428 C>T), RS1000727215 (15:74110172 C>T), RS1000762644 (15:74129411 C>A,T), RS1000898350 (15:74135900 C>T)

Disease associations

OMIM: gene MIM:614179 | disease phenotypes: MIM:616409

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies/dysmorphic syndrome	Moderate	Autosomal recessive

Mondo (2): developmental and epileptic encephalopathy, 33 (MONDO:0014625), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (1): Non-specific early-onset epileptic encephalopathy (Orphanet:442835)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1821	Blood protein levels	2.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases mutagenesis, affects methylation	2
beauvericin	affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
1,6-hexamethylene diisocyanate	increases methylation	1
tetrabromobisphenol A	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
tebuconazole	decreases expression	1
enniatins	affects cotreatment, decreases expression	1
2-palmitoylglycerol	increases expression	1
Acetaminophen	increases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	increases methylation	1
Phthalic Acids	increases methylation	1
Silicon Dioxide	decreases methylation, increases expression	1
Smoke	increases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Tunicamycin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Gold Compounds	decreases expression	1
Thapsigargin	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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