ERLIN2

Summary

ERLIN2 (ER lipid raft associated 2, HGNC:1356) is a protein-coding gene on chromosome 8p11.23, encoding Erlin-2 (O94905). Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.

This gene encodes a member of the SPFH domain-containing family of lipid raft-associated proteins. The encoded protein is localized to lipid rafts of the endoplasmic reticulum and plays a critical role in inositol 1,4,5-trisphosphate (IP3) signaling by mediating ER-associated degradation of activated IP3 receptors. Mutations in this gene are a cause of spastic paraplegia-18 (SPG18). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 11160 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary spastic paraplegia 18 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 225 total — 20 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• MANE Select transcript: NM_007175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1356
Approved symbol	ERLIN2
Name	ER lipid raft associated 2
Location	8p11.23
Locus type	gene with protein product
Status	Approved
Aliases	NET32, Erlin-2
Ensembl gene	ENSG00000147475
Ensembl biotype	protein_coding
OMIM	611605
Entrez	11160

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000335171, ENST00000518526, ENST00000518586, ENST00000519638, ENST00000519872, ENST00000521644, ENST00000521993, ENST00000523107, ENST00000523887, ENST00000647813, ENST00000648919, ENST00000861237, ENST00000861238, ENST00000861239, ENST00000861240, ENST00000861241, ENST00000861242, ENST00000861243, ENST00000861244, ENST00000963383, ENST00000963384

RefSeq mRNA: 5 — MANE Select: NM_007175 NM_001003790, NM_001003791, NM_001362878, NM_001362880, NM_007175

CCDS: CCDS34879, CCDS6095

Canonical transcript exons

ENST00000519638 — 12 exons

Exon	Start	End
ENSE00001027993	37751626	37751715
ENSE00001027994	37753450	37753529
ENSE00001027997	37749794	37749852
ENSE00001683883	37750395	37750486
ENSE00002139307	37753915	37758422
ENSE00003516997	37737908	37738029
ENSE00003521630	37741772	37741818
ENSE00003614770	37744571	37744696
ENSE00003622241	37740365	37740446
ENSE00003654515	37744355	37744416
ENSE00003655817	37749559	37749632
ENSE00003836324	37736634	37736678

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 96.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6078 / max 302.5516, expressed in 1817 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
88444	16.7108	1790
88443	3.4937	1545
88445	2.5028	1338
88447	1.0209	476
88442	0.9156	654
88446	0.5174	289
88448	0.2384	87
88449	0.2083	100

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	96.91	gold quality
renal medulla	UBERON:0000362	93.27	gold quality
calcaneal tendon	UBERON:0003701	93.22	gold quality
islet of Langerhans	UBERON:0000006	93.05	gold quality
parotid gland	UBERON:0001831	92.48	gold quality
germinal epithelium of ovary	UBERON:0001304	92.41	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.38	gold quality
bronchial epithelial cell	CL:0002328	92.20	gold quality
adrenal tissue	UBERON:0018303	91.84	gold quality
nephron tubule	UBERON:0001231	91.63	gold quality
caput epididymis	UBERON:0004358	91.41	gold quality
stromal cell of endometrium	CL:0002255	91.39	gold quality
corpus epididymis	UBERON:0004359	91.34	gold quality
rectum	UBERON:0001052	91.19	gold quality
renal glomerulus	UBERON:0000074	91.06	gold quality
metanephric glomerulus	UBERON:0004736	90.97	gold quality
parietal pleura	UBERON:0002400	90.92	gold quality
mammary duct	UBERON:0001765	90.88	gold quality
pigmented layer of retina	UBERON:0001782	90.66	gold quality
seminal vesicle	UBERON:0000998	90.61	gold quality
pancreas	UBERON:0001264	90.45	gold quality
cranial nerve II	UBERON:0000941	90.40	gold quality
body of pancreas	UBERON:0001150	90.14	gold quality
epithelium of bronchus	UBERON:0002031	90.14	gold quality
epithelium of mammary gland	UBERON:0003244	90.04	gold quality
bronchus	UBERON:0002185	89.95	gold quality
pleura	UBERON:0000977	89.65	gold quality
tibia	UBERON:0000979	89.48	gold quality
cortex of kidney	UBERON:0001225	89.45	gold quality
thoracic mammary gland	UBERON:0005200	89.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.80
E-MTAB-7606	no	526.19

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

186 targeting ERLIN2, 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-4283	100.00	66.42	2097
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-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-15A-5P	99.90	72.80	2787

Literature-anchored findings (GeneRIF, showing 25)

• Erlin-1 and erlin-2 are novel members of the prohibitin family of proteins that define lipid-raft-like domains of the ER. (PMID:16835267)
• SPFH2 as a key endoplasmic reticulum associated degradation pathway component and suggest that it may act as a substrate recognition factor. (PMID:17502376)
• Results suggest that this novel SPFH1/2 complex is a recognition factor that targets IP(3)Rs and perhaps other substrates for ERAD. (PMID:19240031)
• m3 receptor-expressing HeLa cells are a valuable system for studying IP(3) receptor ERAD, and suggest that the SPFH1/2 complex is a factor that selectively mediates the ERAD of activated IP(3) receptors. (PMID:19751772)
• The gene encodes endoplasmic reticulum (ER) lipid raft-associated protein 2 that mediates the ER-associated degradation of activated inositol 1,4,5-trisphosphate receptors and other substrates. (PMID:21330303)
• study describes an extended consanguineous Saudi family in which hereditary spastic paraplegia is linked to SPG18, an autosomal recessive locus, and show it is associated with a nullimorphic deletion of ERLIN2 (PMID:21796390)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• ERLIN2 may confer a selective growth advantage for breast cancer cells by facilitating a cytoprotective response to various cellular stresses associated with oncogenesis. (PMID:22681620)
• a novel role for ERLIN2 in supporting cancer cell growth by promoting the activation of the key lipogenic regulator SREBP1c and the production of cytosolic lipid droplets. (PMID:22690709)
• a novel brain gamma-secretase associated protein , erlin-2, that resides in detergent resistant membranes and affects amyloid beta-peptide production. (PMID:22771797)
• ERLIN2 was found to be responsible for causing hereditary spastic paraplegia in a Saudi family. (PMID:23085305)
• ERLIN2 loss on cell growth may advance understanding of the mechanism behind motor neuron degeneration in primary lateral sclerosis (PMID:23109145)
• Erlin-2 and the related erlin-1 were found to negatively regulate cholesterol and fatty acid biosynthesis in cultured cell models when the proteins were depleted by RNAi. The proteins also selectively bound cholesterol. (PMID:24217618)
• Here we show that the multimeric ER proteins erlins-1 and -2 are additional sterol regulatory element binding protein regulators. (PMID:24217618)
• Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18 (PMID:27824013)
• Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset Amyotrophic lateral sclerosis (ALS) , starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. (PMID:29453415)
• Biallelic variants in ERLIN2 are known to cause recessive HSP type SPG18. Here, the first two families with an autosomal dominant, pure form of HSP caused by a novel ERLIN2 heterozygous missense variant are described. These findings expand the mutational and inheritance spectrum of SPG18. (PMID:29528531)
• An autosomal dominant ERLIN2 mutation leads to a pure HSP phenotype distinct from the autosomal recessive ERLIN2 mutations (SPG18). (PMID:32094424)
• Expansion of the genetic landscape of ERLIN2-related disorders. (PMID:32147972)
• Molecular and Immune Characteristics for Lung Adenocarcinoma Patients With ERLIN2 Overexpression. (PMID:33424830)
• Usp25-Erlin1/2 activity limits cholesterol flux to restrict virus infection. (PMID:37683630)
• A novel autosomal dominant ERLIN2 variant activates endoplasmic reticulum stress in a Chinese HSP family. (PMID:37752894)
• KCNN1 promotes proliferation and metastasis of breast cancer via ERLIN2-mediated stabilization and K63-dependent ubiquitination of Cyclin B1. (PMID:37831636)
• Novel ERLIN2 variant expands the phenotype of Spastic Paraplegia 18. (PMID:38159148)
• The erlin1/erlin2 complex binds to and stabilizes phosphatidylinositol 3-phosphate and regulates autophagy. (PMID:39018973)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	erlin2	ENSDARG00000086523
mus_musculus	Erlin2	ENSMUSG00000031483
rattus_norvegicus	Erlin2	ENSRNOG00000013763
caenorhabditis_elegans		WBGENE00016592

Paralogs (1): ERLIN1 (ENSG00000107566)

Protein

Protein identifiers

Erlin-2 — O94905 (reviewed: O94905)

Alternative names: Endoplasmic reticulum lipid raft-associated protein 2, Stomatin-prohibitin-flotillin-HflC/K domain-containing protein 2

All UniProt accessions (4): O94905, A0A384ME54, E5RHW4, E5RJ09

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1. Promotes sterol-accelerated ERAD of HMGCR probably implicating an AMFR/gp78-containing ubiquitin ligase complex. Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. May promote ER retention of the SCAP-SREBF complex.

Subunit / interactions. Forms a heteromeric complex with ERLIN1. In complex with ERLIN1, interacts with RNF170. Interacts with activated ITPR1, independently of the degree of ITPR1 polyubiquitination. Interacts with SCAP, INSIG1, SREBF1 and SREBF2 under cholesterol sufficiency conditions; indicative for an association with the SCAP-SREBP-INSIG complex. Probably part of an AMFR/gp78 and INSIG1-containing ubiquitin ligase complex involved in ERAD of HMGCR. Interacts with TMUB1; TMUB1 bridges the association with AMFR. Interacts with SYVN1 and RNF139. Interacts with TMEM259. Interacts with TMEM41B.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. Deubiquitinated by USP25; leading to stabilization.

Disease relevance. Spastic paraplegia 18B, autosomal recessive (SPG18B) [MIM:611225] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG18B is a severe form with onset in early childhood. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 18A, autosomal dominant (SPG18A) [MIM:620512] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG18A is a pure form. Age at onset of symptoms varies considerably from childhood to adulthood. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the band 7/mec-2 family.

Isoforms (3)

UniProt ID	Names	Canonical?
O94905-1	1	yes
O94905-2	2
O94905-3	3

RefSeq proteins (5): NP_001003790, NP_001003791, NP_001349807, NP_001349809, NP_009106* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001107	Band_7	Domain
IPR033294	Erlin1/2	Family
IPR036013	Band_7/SPFH_dom_sf	Homologous_superfamily

Pfam: PF01145

UniProt features (18 total): sequence variant 5, splice variant 4, topological domain 2, chain 1, mutagenesis site 1, sequence conflict 1, transmembrane region 1, region of interest 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9WFF	ELECTRON MICROSCOPY	2.12
9VVJ	ELECTRON MICROSCOPY	2.6
9VVG	ELECTRON MICROSCOPY	2.7
9O9U	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94905-F1	85.35	0.70

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 (1): 267

Glycosylation sites (1): 106

Mutagenesis-validated functional residues (1):

Position	Phenotype
106	loss of glycosylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-8853336	Signaling by plasma membrane FGFR1 fusions
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)

MSigDB gene sets: 398 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, ACTACCT_MIR196A_MIR196B, TAATAAT_MIR126, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_255, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (8): cholesterol metabolic process (GO:0008203), SREBP signaling pathway (GO:0032933), ERAD pathway (GO:0036503), regulation of cholesterol biosynthetic process (GO:0045540), negative regulation of cholesterol biosynthetic process (GO:0045541), negative regulation of fatty acid biosynthetic process (GO:0045717), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202)

GO Molecular Function (3): cholesterol binding (GO:0015485), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (7): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), protein-containing complex (GO:0032991), membrane raft (GO:0045121), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Transport of small molecules	1
Signaling by FGFR in disease	1
ABC transporter disorders	1
FGFR1 mutant receptor activation	1
Regulation of PD-L1(CD274) Post-translational modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cholesterol biosynthetic process	2
cytoplasm	2
cellular anatomical structure	2
sterol metabolic process	1
secondary alcohol metabolic process	1
ER-nucleus signaling pathway	1
cellular response to sterol depletion	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
negative regulation of cholesterol metabolic process	1
negative regulation of sterol biosynthetic process	1
negative regulation of alcohol biosynthetic process	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
primary metabolic process	1
lipid metabolic process	1
sterol binding	1
alcohol binding	1
ubiquitin-like protein ligase binding	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cellular_component	1
membrane microdomain	1

Protein interactions and networks

STRING

1479 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERLIN2	PHB1	P35232	988
ERLIN2	ERLIN1	O75477	917
ERLIN2	AMFR	P26442	840
ERLIN2	RNF170	Q96K19	752
ERLIN2	TMUB1	Q9BVT8	747
ERLIN2	ITPR1	Q14643	708
ERLIN2	SEL1L	Q9UBV2	659
ERLIN2	DDHD2	O94830	657
ERLIN2	PLPBP	O94903	618
ERLIN2	ZNF703	Q9H7S9	613
ERLIN2	FAF2	Q96CS3	612
ERLIN2	STOM	P27105	612
ERLIN2	OS9	Q13438	609
ERLIN2	FAM8A1	Q9UBU6	594
ERLIN2	ERLEC1	Q96DZ1	592

IntAct

227 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
ERLIN1	ERLIN2	psi-mi:“MI:0915”(physical association)	0.740
ERLIN2	ERLIN1	psi-mi:“MI:0914”(association)	0.740
ERLIN1	ERLIN2	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
AMFR	ERLIN2	psi-mi:“MI:0915”(physical association)	0.660
AMFR	ERLIN2	psi-mi:“MI:0914”(association)	0.660
ERLIN2	AMFR	psi-mi:“MI:0915”(physical association)	0.660
ERLIN2	TMUB1	psi-mi:“MI:0915”(physical association)	0.660
ERLIN2	TMUB1	psi-mi:“MI:0914”(association)	0.660
ERLIN2	AMFR	psi-mi:“MI:0914”(association)	0.660
TMUB1	ERLIN2	psi-mi:“MI:0915”(physical association)	0.660
TMUB1	ERLIN2	psi-mi:“MI:0914”(association)	0.660
ERLIN2	HSPA5	psi-mi:“MI:0914”(association)	0.640
RAB8A	WDR91	psi-mi:“MI:0914”(association)	0.600
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
SYVN1	ERLIN2	psi-mi:“MI:0915”(physical association)	0.560
RNF170	ERLIN1	psi-mi:“MI:0914”(association)	0.530

BioGRID (464): TMUB1 (Affinity Capture-MS), SRPRB (Affinity Capture-MS), CASP8 (Affinity Capture-MS), CANX (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCDC47 (Affinity Capture-MS), ATP2A2 (Affinity Capture-MS), SEC61B (Affinity Capture-MS), HSP90B1 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), ERLIN1 (Affinity Capture-MS), UBC (Affinity Capture-MS), HSPA4 (Affinity Capture-MS), CSE1L (Affinity Capture-MS), TRIM28 (Affinity Capture-MS)

ESM2 similar proteins: A3QK16, B5DEH2, B5DGH9, B9N1F9, O54734, O54956, O75477, O89000, O94905, P11029, P11497, P35232, P48440, P67778, P67779, P84173, Q05AY2, Q12882, Q13085, Q1LUA8, Q1RMU4, Q28007, Q28559, Q28943, Q28DX1, Q28J34, Q39258, Q3B8M3, Q3T165, Q58EG2, Q5R7C5, Q5R895, Q5RCJ9, Q5SWU9, Q5XH03, Q5ZLA5, Q641X8, Q641Y0, Q6DKC0, Q6DRI1

Diamond homologs: A3QK16, A3QMC6, B5DEH2, O75477, O94905, Q1RMU4, Q28DX1, Q28J34, Q58EG2, Q5R7C5, Q5RCJ9, Q5XH03, Q6DKC0, Q8BFZ9, Q91X78

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ERLIN2	“form complex”	Erlin	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 216 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Calnexin/calreticulin cycle	5	25.9×	2e-04
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	6	18.4×	2e-04
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	5	14.3×	2e-03
Defective CFTR causes cystic fibrosis	7	11.1×	4e-04
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	6	8.4×	6e-03
R-HSA-425393	7	6.6×	7e-03
Anchoring of the basal body to the plasma membrane	8	6.5×	3e-03
ABC-family protein mediated transport	7	6.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
bicarbonate transport	5	22.2×	1e-03
ERAD pathway	17	17.0×	2e-13
regulation of intracellular pH	5	16.6×	3e-03
transmembrane transport	14	13.0×	2e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	11
Uncertain significance	92
Likely benign	64
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071452	NM_007175.8(ERLIN2):c.367G>T (p.Glu123Ter)	Pathogenic
2579114	NM_007175.8(ERLIN2):c.47_48delinsAA (p.Cys16Ter)	Pathogenic
2583112	NM_007175.8(ERLIN2):c.386G>C (p.Ser129Thr)	Pathogenic
2663863	NM_007175.8(ERLIN2):c.660del (p.Val221fs)	Pathogenic
2735636	NM_007175.8(ERLIN2):c.303del (p.Val100_Tyr101insTer)	Pathogenic
280398	NM_007175.8(ERLIN2):c.17del (p.Ala6fs)	Pathogenic
2845897	NM_007175.8(ERLIN2):c.179dup (p.Ser61fs)	Pathogenic
30913	NM_007175.8(ERLIN2):c.812_813insAC (p.Asn272fs)	Pathogenic
374613	NM_007175.8(ERLIN2):c.237-1G>A	Pathogenic
4806226	NM_007175.8(ERLIN2):c.684del (p.Tyr229fs)	Pathogenic
639125	NM_007175.8(ERLIN2):c.46del (p.Cys16fs)	Pathogenic
817651	NM_007175.8(ERLIN2):c.353del (p.Asn118fs)	Pathogenic
834707	NM_007175.8(ERLIN2):c.303T>A (p.Tyr101Ter)	Pathogenic
92113	NM_007175.8(ERLIN2):c.499-1G>T	Pathogenic
959955	NM_007175.8(ERLIN2):c.853A>T (p.Lys285Ter)	Pathogenic
989002	NM_007175.8(ERLIN2):c.374A>G (p.Asn125Ser)	Pathogenic
989003	NM_007175.8(ERLIN2):c.430A>G (p.Ile144Val)	Pathogenic
989004	NM_007175.8(ERLIN2):c.799A>G (p.Lys267Glu)	Pathogenic
989005	NM_007175.8(ERLIN2):c.819G>A (p.Lys273=)	Pathogenic
989006	NM_007175.8(ERLIN2):c.877A>G (p.Ser293Gly)	Pathogenic
1180600	NM_007175.8(ERLIN2):c.549del (p.Asn182_Tyr183insTer)	Likely pathogenic
1467186	NM_007175.8(ERLIN2):c.237-2A>G	Likely pathogenic
1992126	NM_007175.8(ERLIN2):c.207T>G (p.Asp69Glu)	Likely pathogenic
2010956	NM_007175.8(ERLIN2):c.532G>A (p.Ala178Thr)	Likely pathogenic
3779628	NM_007175.8(ERLIN2):c.107+2T>C	Likely pathogenic
435090	NM_007175.8(ERLIN2):c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA	Likely pathogenic
4537456	NM_007175.8(ERLIN2):c.819+2T>C	Likely pathogenic
4540447	NM_007175.8(ERLIN2):c.969_973del (p.Ser324fs)	Likely pathogenic
4685121	NM_007175.8(ERLIN2):c.207T>A (p.Asp69Glu)	Likely pathogenic
4759352	NM_007175.8(ERLIN2):c.988del (p.Glu330fs)	Likely pathogenic

SpliceAI

1975 predictions. Top by Δscore:

Variant	Effect	Δscore
8:37744353:A:AG	acceptor_gain	1.0000
8:37744354:G:GG	acceptor_gain	1.0000
8:37744569:A:AG	acceptor_gain	1.0000
8:37744570:G:GA	acceptor_gain	1.0000
8:37744570:GT:G	acceptor_gain	1.0000
8:37744692:GTTTG:G	donor_gain	1.0000
8:37749552:A:AG	acceptor_gain	1.0000
8:37749554:TCCA:T	acceptor_loss	1.0000
8:37749557:A:AG	acceptor_gain	1.0000
8:37749558:G:GA	acceptor_gain	1.0000
8:37749558:GATC:G	acceptor_gain	1.0000
8:37749558:GATCA:G	acceptor_gain	1.0000
8:37749630:CAAG:C	donor_loss	1.0000
8:37749631:AAGT:A	donor_loss	1.0000
8:37749632:AGTA:A	donor_loss	1.0000
8:37749633:G:GG	donor_gain	1.0000
8:37749634:T:A	donor_loss	1.0000
8:37749793:GGCT:G	acceptor_gain	1.0000
8:37749849:TGATG:T	donor_loss	1.0000
8:37749850:GAT:G	donor_gain	1.0000
8:37749850:GATGT:G	donor_loss	1.0000
8:37749852:TG:T	donor_loss	1.0000
8:37749853:G:GG	donor_gain	1.0000
8:37749853:GTGA:G	donor_loss	1.0000
8:37749854:T:G	donor_loss	1.0000
8:37749855:GAGTA:G	donor_loss	1.0000
8:37749856:AGTAT:A	donor_loss	1.0000
8:37750453:G:GT	donor_gain	1.0000
8:37750470:G:GT	donor_gain	1.0000
8:37750473:G:GT	donor_gain	1.0000

AlphaMissense

2247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:37738007:G:A	G29R	1.000
8:37738007:G:C	G29R	1.000
8:37738008:G:A	G29E	1.000
8:37738016:G:T	G32W	1.000
8:37741808:T:A	C76S	1.000
8:37741808:T:C	C76R	1.000
8:37741809:G:A	C76Y	1.000
8:37741809:G:C	C76S	1.000
8:37741809:G:T	C76F	1.000
8:37741810:T:G	C76W	1.000
8:37741811:G:A	G77R	1.000
8:37741811:G:C	G77R	1.000
8:37741811:G:T	G77W	1.000
8:37741812:G:A	G77E	1.000
8:37744359:G:C	G81R	1.000
8:37744359:G:T	G81C	1.000
8:37744360:G:A	G81D	1.000
8:37744397:C:A	N93K	1.000
8:37744397:C:G	N93K	1.000
8:37744607:A:T	D112V	1.000
8:37744616:T:C	L115P	1.000
8:37744619:T:A	I116N	1.000
8:37744633:C:G	H121D	1.000
8:37744636:C:G	H122D	1.000
8:37744643:T:C	L124P	1.000
8:37744647:C:A	N125K	1.000
8:37744647:C:G	N125K	1.000
8:37744649:A:C	Q126P	1.000
8:37744654:T:A	C128S	1.000
8:37744654:T:C	C128R	1.000

dbSNP variants (sampled 300 via entrez): RS1000051305 (8:37752797 A>G), RS1000072683 (8:37750569 G>A), RS1000262965 (8:37757246 A>G), RS1000330329 (8:37746101 CTT>C,CT), RS1000468472 (8:37739737 A>G), RS1000917283 (8:37743942 T>A), RS1000930803 (8:37744240 C>T), RS1001004039 (8:37758216 T>C), RS1001055946 (8:37751239 C>A), RS1001107253 (8:37736384 G>A), RS1001386205 (8:37744617 C>T), RS1001454827 (8:37758571 C>A,T), RS1001606083 (8:37747689 G>C,T), RS1001721172 (8:37754299 G>A), RS1001782689 (8:37739452 C>A)

Disease associations

OMIM: gene MIM:611605 | disease phenotypes: MIM:303350, MIM:620512, MIM:611225

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary spastic paraplegia 18	Strong	Autosomal recessive
spastic paraplegia 18b, autosomal recessive	Strong	Autosomal recessive
spastic paraplegia 18a, autosomal dominant	Strong	Autosomal dominant
juvenile primary lateral sclerosis	Supportive	Autosomal recessive
recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary spastic paraplegia 18	Limited	AD
hereditary spastic paraplegia 18	Definitive	AR

Mondo (7): hereditary spastic paraplegia 18 (MONDO:0012639), congenital nervous system disorder (MONDO:0002320), hereditary spastic paraplegia (MONDO:0019064), spastic paraplegia 18a, autosomal dominant (MONDO:0957788), spastic paraplegia 18b, autosomal recessive (MONDO:0700309), juvenile primary lateral sclerosis (MONDO:0011663), recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome (MONDO:0017232)

Orphanet (2): Autosomal spastic paraplegia type 18 (Orphanet:209951), Hereditary spastic paraplegia (Orphanet:685)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000014	Abnormality of the bladder
HP:0000020	Urinary incontinence
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000322	Short philtrum
HP:0000377	Abnormal pinna morphology
HP:0000486	Strabismus
HP:0000574	Thick eyebrow
HP:0000664	Synophrys
HP:0000666	Horizontal nystagmus
HP:0000763	Sensory neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001263	Global developmental delay
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001583	Rotary nystagmus
HP:0001760	Abnormal foot morphology
HP:0001761	Pes cavus
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002115_11	Axial length	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C536416	Primary lateral sclerosis juvenile (supp.)
C567628	Spastic Paraplegia 18, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739672 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.51	Kd	3055	nM	CHEMBL5653589
5.51	ED50	3055	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148334: Binding affinity to human ERLIN2 incubated for 45 mins by Kinobead based pull down assay	kd	3.0553	uM

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, decreases expression	3
bisphenol F	increases expression, affects cotreatment	2
sodium arsenite	affects methylation, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
cobaltous chloride	decreases expression	1
pentanal	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Benztropine	affects cotreatment, increases expression	1
Cadmium	increases abundance, increases expression	1
Cuprizone	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Diethylstilbestrol	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4700046	Binding	Binding affinity to ERLIN2 in human K562 cells at 1 mM incubated for 2 hrs by LC-MS/MS analysis based pull down assay relative to control	Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors — RSC Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury
NCT05613114	Not specified	COMPLETED	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia
NCT05767268	Not specified	COMPLETED	Assessment of the Psychophysical State During Rehabilitation Treatment With Lokomat
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06156813	Not specified	RECRUITING	Turkish Lower-Extremity Motor Activity Log (LE-MAL)
NCT06229626	Not specified	RECRUITING	Evaluation of an Intensive Training Program for Patients with Hereditary Spastic Paraparesis SPG4/Spast
NCT06260982	Not specified	UNKNOWN	Cognitive Disorders in Hereditary Spastic Paraplegia Type 4
NCT06553976	Not specified	RECRUITING	Spastic Paraplegia - Centers of Excellence Research Network
NCT06572046	Not specified	RECRUITING	STOP-HSP.Net: a Registry for Hereditary Spastic Paraplegia as an Integration Tool for Future Therapeutic Strategies
NCT06573866	Not specified	RECRUITING	Enhancement of Quality of Work And Life
NCT06680063	Not specified	COMPLETED	Correlation Between Clinical Assessment and Neurophysiological Assessment in Spinal Cord Injury