GLE1

Summary

GLE1 (GLE1 RNA export mediator, HGNC:4315) is a protein-coding gene on chromosome 9q34.11, encoding mRNA export factor GLE1 (Q53GS7). Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm. It is a selective cancer dependency (DepMap: 76.2% of cell lines).

This gene encodes a predicted 75-kDa polypeptide with high sequence and structure homology to yeast Gle1p, which is nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)+RNA export. Inhibition of human GLE1L by microinjection of antibodies against GLE1L in HeLa cells resulted in inhibition of poly(A)+RNA export. Immunoflourescence studies show that GLE1L is localized at the nuclear pore complexes. This localization suggests that GLE1L may act at a terminal step in the export of mature RNA messages to the cytoplasm. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lethal arthrogryposis-anterior horn cell disease syndrome (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 766 total — 77 pathogenic, 64 likely-pathogenic
• Phenotypes (HPO): 108
• Cancer dependency (DepMap): dependent in 76.2% of screened cell lines
• MANE Select transcript: NM_001003722

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4315
Approved symbol	GLE1
Name	GLE1 RNA export mediator
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Aliases	hGLE1
Ensembl gene	ENSG00000119392
Ensembl biotype	protein_coding
OMIM	603371
Entrez	2733

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 23 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000309971, ENST00000372770, ENST00000494417, ENST00000682831, ENST00000683044, ENST00000683288, ENST00000683331, ENST00000683748, ENST00000683905, ENST00000684139, ENST00000684210, ENST00000684314, ENST00000684331, ENST00000684463, ENST00000684646, ENST00000898503, ENST00000898504, ENST00000898505, ENST00000898506, ENST00000898507, ENST00000898508, ENST00000898509, ENST00000898510, ENST00000898511, ENST00000937195, ENST00000961293, ENST00000961294, ENST00000961295, ENST00000961296, ENST00000961297, ENST00000961298

RefSeq mRNA: 3 — MANE Select: NM_001003722 NM_001003722, NM_001411013, NM_001499

CCDS: CCDS35154, CCDS6904, CCDS94499

Canonical transcript exons

ENST00000309971 — 16 exons

Exon	Start	End
ENSE00000806966	128522668	128522816
ENSE00000806972	128533513	128533655
ENSE00000806973	128533761	128533951
ENSE00000806974	128536355	128536484
ENSE00000806975	128537986	128538090
ENSE00000806977	128539616	128539698
ENSE00000806978	128540275	128540338
ENSE00001458611	128541102	128542288
ENSE00001458634	128504719	128504904
ENSE00003465979	128523280	128523340
ENSE00003488363	128515529	128515639
ENSE00003603223	128525192	128525423
ENSE00003611694	128523592	128523846
ENSE00003630742	128527179	128527291
ENSE00003662715	128527456	128527525
ENSE00003674736	128508876	128509097

Expression profiles

Bgee: expression breadth ubiquitous, 267 present calls, max score 93.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6223 / max 108.5483, expressed in 1814 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98802	17.6021	1814
98804	0.0202	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.39	gold quality
tendon of biceps brachii	UBERON:0008188	90.32	gold quality
right testis	UBERON:0004534	89.45	gold quality
granulocyte	CL:0000094	89.14	gold quality
left testis	UBERON:0004533	89.14	gold quality
testis	UBERON:0000473	89.00	gold quality
gastrocnemius	UBERON:0001388	88.21	gold quality
sperm	CL:0000019	88.06	gold quality
muscle of leg	UBERON:0001383	87.98	gold quality
monocyte	CL:0000576	87.86	gold quality
leukocyte	CL:0000738	87.84	gold quality
ventricular zone	UBERON:0003053	87.61	gold quality
mononuclear cell	CL:0000842	87.59	gold quality
islet of Langerhans	UBERON:0000006	87.56	gold quality
tendon	UBERON:0000043	87.08	gold quality
rectum	UBERON:0001052	86.95	gold quality
ganglionic eminence	UBERON:0004023	86.77	gold quality
male germ cell	CL:0000015	86.30	gold quality
mucosa of transverse colon	UBERON:0004991	86.10	gold quality
blood	UBERON:0000178	85.95	gold quality
lymph node	UBERON:0000029	85.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.45	gold quality
cortical plate	UBERON:0005343	85.32	gold quality
right adrenal gland	UBERON:0001233	85.30	gold quality
skin of leg	UBERON:0001511	85.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.23	gold quality
medial globus pallidus	UBERON:0002477	85.20	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.05	gold quality
skin of abdomen	UBERON:0001416	85.03	gold quality
parotid gland	UBERON:0001831	84.82	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting GLE1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• The unique carboxyl-terminal 43 amino acid region of the hGle1B isoform mediates binding to the C-terminal non-phenylalanine- glycine region of the nucleoporin hCG1/NPL1. (PMID:16000379)
• Mutations in mRNA export mediator GLE1 result in fetal motoneuron disease. (PMID:18204449)
• Dbp5, Gle1-IP6 and Nup159: a working model for mRNP export. (PMID:22064466)
• defective zebrafish GLE1 function in human LCCS1 results in both neurogenic and non-neurogenic defects linked to the apoptosis of proliferative organ precursors (PMID:22357925)
• Report documents a requirement for Gle1 self-association during mRNA export and uncover molecular defects underlying a lethal human disease lethal congenital contracture syndrome-1. (PMID:24243016)
• Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are associated with defective Gle1 function during the export of mRNA. [review] (PMID:24275432)
• We report the identification of the first heterozygous mutations in GLE1 ever found to be associated with amyotrophic lateral sclerosis. (PMID:25343993)
• Role for Gle1A during stress granule formation and translation regulation during environmental stress responses is examined. (PMID:25694449)
• Restoration of miR-127-3p and miR-376a-3p counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells by targeting COA1, GLE1 and PDIA6. (PMID:26655997)
• It was concluded that the amyotrophic lateral sclerosis-linked Gle1-c.1965-2A>C mutation generates a protein isoform capable of both Gle1A- and Gle1B-ascribed functions, and thereby uncoupled from normal mechanisms of Gle1 regulation. (PMID:26776475)
• We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein (PMID:27684565)
• Data indicate 2 siblings with a homozygous p.I684T mutation in RNA export mediator (GLE1). (PMID:28657126)
• We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties, and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C-terminus of GLE1 that are predicted to disrupt protein-protein interaction or GLE1 protein targeting. (PMID:28884921)
• Pathogenic variants in the GLE1 gene are rare in Chinese ALS patients. (PMID:29398120)
• These results imply that DBP5, GLE1 and IP6 have a conserved and individual function in the cytoplasmic mRNA expression. Variations in phenotype are due to the difference in each function of DBP5, GLE1 and IPPK in intracellular mRNA metabolism. (PMID:29746542)
• Results found that Nup159 did not accelerate ADP release, while Gle1 actually slowed it independently of Mg(2+) which is not consistent with Nup159 acting as a nucleotide exchange factor to promote ADP release and Dbp5 ATPase cycling. Instead, in the presence of Nup159, the interaction between Gle1 and ADP-bound Dbp5 was found more reduced, suggesting that Nup159 alters the Dbp5-Gle1 to aid Gle1 release from Dbp5. (PMID:29782832)
• This study supports models wherein SGs play a role in cell evasion of apoptosis and further reveal Gle1A and SG functions as targets for clinical approaches directed at chemoresistant/refractory cells. (PMID:30262214)
• Mitogen-activated protein kinases and glycogen synthase kinase 3 phosphorylate Gle1A and thereby coordinate stress granule dynamics by altering DDX3 function. (PMID:30429220)
• preliminary data show an intriguing expression profile of Gle1, MART3 and FUS genes in Spinal muscular atrophy (SMA), and suggest a critical role of FUS protein in the SMA pathogenesis. (PMID:30565205)
• Extension of the phenotypic spectrum of GLE1-related disorders to a mild congenital form resembling congenital myopathy. (PMID:32537934)
• Nucleocytoplasmic shuttling of Gle1 impacts DDX1 at transcription termination sites. (PMID:32755435)
• Biallelic variants in GLE1 with survival beyond neonatal period. (PMID:32954510)
• Functions of Gle1 are governed by two distinct modes of self-association. (PMID:32981894)
• Phosphorylation impacts GLE1 nuclear localization and association with DDX1. (PMID:37801910)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	gle1	ENSDARG00000043559
mus_musculus	Gle1	ENSMUSG00000019715
rattus_norvegicus	Gle1l1	ENSRNOG00000012652
rattus_norvegicus	Gle1-ps1	ENSRNOG00000053311
drosophila_melanogaster	Gle1	FBGN0033316

Protein

Protein identifiers

mRNA export factor GLE1 — Q53GS7 (reviewed: Q53GS7)

Alternative names: GLE1 RNA export mediator, GLE1-like protein, Nucleoporin GLE1

All UniProt accessions (10): Q53GS7, A0A804HI94, A0A804HIJ1, A0A804HJ00, A0A804HJ70, A0A804HJB3, A0A804HJF3, A0A804HJY9, A0A804HK09, A0A804HLL7

UniProt curated annotations — full annotation on UniProt →

Function. Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm. May be involved in the terminal step of the mRNA transport through the nuclear pore complex (NPC).

Subunit / interactions. Associated with the NPC, however it may not be a stable component of the NPC complex since it shuttles between the nucleus and the cytoplasm. Interacts with nuclear pore complex proteins NUP155 and NUP42. Isoform 2 does not interact with NUP42. Able to form a heterotrimer with NUP155 and NUP42 in vitro.

Subcellular location. Nucleus. Cytoplasm Cytoplasm. Nuclear pore complex.

Disease relevance. Lethal congenital contracture syndrome 1 (LCCS1) [MIM:253310] A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non-progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS1 patients manifest early fetal hydrops and akinesia, micrognathia, pulmonary hypoplasia, pterygia, and multiple joint contractures. It leads to prenatal death. The disease is caused by variants affecting the gene represented in this entry. Congenital arthrogryposis with anterior horn cell disease (CAAHD) [MIM:611890] An autosomal recessive disorder characterized by fetal akinesia, arthrogryposis and motor neuron loss. The fetus often survives delivery, but dies early as a result of respiratory failure. Neuropathological findings resemble those of lethal congenital contracture syndrome type 1, but are less severe. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Major isoform.

Similarity. Belongs to the GLE1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53GS7-1	1, hGle1B	yes
Q53GS7-2	2, hGle1A

RefSeq proteins (3): NP_001003722, NP_001397942, NP_001490 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012476	GLE1	Family
IPR038506	GLE1-like_sf	Homologous_superfamily

Pfam: PF07817

UniProt features (50 total): helix 19, sequence variant 7, region of interest 5, turn 4, modified residue 3, sequence conflict 3, splice variant 2, strand 2, coiled-coil region 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6B4F	X-RAY DIFFRACTION	2.81
6B4J	X-RAY DIFFRACTION	3.4
6B4I	X-RAY DIFFRACTION	3.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53GS7-F1	79.55	0.47

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 (3): 41, 88, 99

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript

MSigDB gene sets: 393 (showing top): MORF_FLT1, MORF_MSH3, MORF_BRCA1, MORF_ATRX, AMIT_SERUM_RESPONSE_20_MCF10A, MORF_ESR1, MORF_RAD51L3, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_NUCLEAR_TRANSPORT, MODULE_379, REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA, GOCC_CENTROSOME, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, MORF_ETV3, GOBP_NUCLEAR_EXPORT

GO Biological Process (5): mRNA export from nucleus (GO:0006406), nucleocytoplasmic transport (GO:0006913), protein transport (GO:0015031), poly(A)+ mRNA export from nucleus (GO:0016973), mRNA transport (GO:0051028)

GO Molecular Function (5): inositol hexakisphosphate binding (GO:0000822), phospholipid binding (GO:0005543), translation initiation factor binding (GO:0031369), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (13): obsolete extracellular space (GO:0005615), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), membrane (GO:0016020), nuclear membrane (GO:0031965), ciliary basal body (GO:0036064), nuclear pore cytoplasmic filaments (GO:0044614), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of Mature Transcript to Cytoplasm	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
microtubule organizing center	3
protein binding	2
nucleus	2
nuclear envelope	2
nuclear protein-containing complex	2
intracellular membraneless organelle	2
RNA export from nucleus	1
gene expression	1
mRNA transport	1
nuclear transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
mRNA export from nucleus	1
RNA transport	1
anion binding	1
alcohol binding	1
lipid binding	1
binding	1
endomembrane system	1
organelle envelope	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
cytoplasm	1
organelle membrane	1
cilium	1
nuclear pore	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLE1	SON	P18583	927
GLE1	NUP214	P35658	924
GLE1	NUP155	O75694	920
GLE1	RAE1	P78406	914
GLE1	NUP42	O15504	907
GLE1	NUP88	Q99567	852
GLE1	PIP5K1C	O60331	835
GLE1	RANBP2	P49792	792
GLE1	NXF1	Q9UBU9	781
GLE1	EIF4A1	P04765	779
GLE1	PIP4K2A	P48426	775
GLE1	XPO1	O14980	721
GLE1	RGPD1	P0C839	718
GLE1	EIF4A2	Q14240	717
GLE1	NUP107	P57740	711

IntAct

287 interactions, top by confidence:

A	B	Type	Score
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
EIF3F	GLE1	psi-mi:“MI:0915”(physical association)	0.570
CCNC	GLE1	psi-mi:“MI:0915”(physical association)	0.560
CLCN7	GLE1	psi-mi:“MI:0915”(physical association)	0.560
DAXX	GLE1	psi-mi:“MI:0915”(physical association)	0.560
TIMM8A	GLE1	psi-mi:“MI:0915”(physical association)	0.560
FANCG	GLE1	psi-mi:“MI:0915”(physical association)	0.560
FYN	GLE1	psi-mi:“MI:0915”(physical association)	0.560
HSD3B2	GLE1	psi-mi:“MI:0915”(physical association)	0.560
MAOB	GLE1	psi-mi:“MI:0915”(physical association)	0.560
NFE2	GLE1	psi-mi:“MI:0915”(physical association)	0.560
PCDHGC3	GLE1	psi-mi:“MI:0915”(physical association)	0.560
SMARCB1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
TERF1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
TSNAX	GLE1	psi-mi:“MI:0915”(physical association)	0.560
COPS3	GLE1	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
VAMP4	GLE1	psi-mi:“MI:0915”(physical association)	0.560
STX11	GLE1	psi-mi:“MI:0915”(physical association)	0.560
	GLE1	psi-mi:“MI:0915”(physical association)	0.560
SNAP91	GLE1	psi-mi:“MI:0915”(physical association)	0.560
STUB1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
NOD1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
NEBL	GLE1	psi-mi:“MI:0915”(physical association)	0.560
BATF	GLE1	psi-mi:“MI:0915”(physical association)	0.560
RASSF1	GLE1	psi-mi:“MI:0915”(physical association)	0.560
MTF2	GLE1	psi-mi:“MI:0915”(physical association)	0.560
PDS5A	GLE1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (199): GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Reconstituted Complex), GLE1 (FRET), GLE1 (Affinity Capture-MS), GLE1 (Proximity Label-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS), GLE1 (Affinity Capture-MS)

ESM2 similar proteins: A1A4V9, A2A8U2, A4IFI1, A8E4X8, B0BMZ6, F1R7R1, G5E8P0, O75161, P12755, P59017, P59240, P85299, P97432, Q14DQ1, Q2HJA5, Q3B7M3, Q3U0L2, Q3ZBK7, Q3ZK22, Q53GS7, Q569K6, Q58DT5, Q5FVG6, Q5RAS2, Q5SNT2, Q5T7N3, Q5XI52, Q60698, Q6NZQ0, Q80U62, Q812A5, Q8C0R7, Q8C190, Q8CC12, Q8IWY9, Q8IYY4, Q8N9B5, Q8NFW9, Q8R1F1, Q8R322

Diamond homologs: Q0WPZ7, Q3ZBK7, Q4KLN4, Q53GS7, Q5RAS2, Q6DRB1, Q8R322, Q9V4W1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
GLE1	“form complex”	NPC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
Nuclear import of Rev protein	8	44.8×	2e-09
Transport of Ribonucleoproteins into the Host Nucleus	7	41.6×	2e-08
NEP/NS2 Interacts with the Cellular Export Machinery	7	40.4×	2e-08
NS1 Mediated Effects on Host Pathways	8	38.1×	4e-09
Transport of the SLBP independent Mature mRNA	7	38.1×	3e-08
IPs transport between nucleus and cytosol	6	38.1×	2e-07
IP3 and IP4 transport between cytosol and nucleus	6	38.1×	2e-07
IP6 and IP7 transport between cytosol and nucleus	6	38.1×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
nucleocytoplasmic transport	5	24.2×	5e-04
mRNA export from nucleus	5	18.2×	1e-03
mRNA transport	5	16.2×	2e-03
protein import into nucleus	7	12.4×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	77
Likely pathogenic	64
Uncertain significance	140
Likely benign	394
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071969	NC_000009.11:g.(?131295782)(131296240_?)del	Pathogenic
1072793	NM_001003722.2(GLE1):c.911del (p.Thr304fs)	Pathogenic
1072925	NM_001003722.2(GLE1):c.1149_1153del (p.Gln383fs)	Pathogenic
1074199	NM_001003722.2(GLE1):c.1411C>T (p.Gln471Ter)	Pathogenic
1074819	NM_001003722.2(GLE1):c.199_202del (p.Ser67fs)	Pathogenic
1076581	NM_001003722.2(GLE1):c.1297del (p.Ile433fs)	Pathogenic
1350943	NM_001003722.2(GLE1):c.590_591del (p.Glu197fs)	Pathogenic
1354032	NC_000009.11:g.(?131284937)(131296240_?)del	Pathogenic
1362319	NM_001003722.2(GLE1):c.96del (p.Glu33fs)	Pathogenic
1378605	NM_001003722.2(GLE1):c.1360_1361delinsTA (p.Gly454Ter)	Pathogenic
1420797	NM_001003722.2(GLE1):c.990dup (p.Arg331fs)	Pathogenic
1421411	NM_001003722.2(GLE1):c.919_920del (p.Gln308fs)	Pathogenic
1421553	NM_001003722.2(GLE1):c.1869dup (p.Asp624Ter)	Pathogenic
1451778	NM_001003722.2(GLE1):c.1166G>A (p.Trp389Ter)	Pathogenic
1452661	NM_001003722.2(GLE1):c.327del (p.Asp110fs)	Pathogenic
1452667	NC_000009.11:g.(?131287461)(131289814_?)del	Pathogenic
1452751	NM_001003722.2(GLE1):c.831dup (p.Ala278fs)	Pathogenic
1455208	NM_001003722.2(GLE1):c.1279dup (p.Thr427fs)	Pathogenic
1455968	NM_001003722.2(GLE1):c.1092dup (p.Ala365fs)	Pathogenic
1456784	NM_001003722.2(GLE1):c.560_561insAGCTGACTCCCTTAGAGCAAAGGATAGACAGCCACCATTACCAAATACCATTTTTGCATGGGGATTGTGCAGCTGGCAGTGTTCCTGCCCCAGCATGGCACCTTANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGAATTCCAGGACTT (p.Arg188fs)	Pathogenic
1456923	NM_001003722.2(GLE1):c.1170C>G (p.Tyr390Ter)	Pathogenic
1931477	NM_001003722.2(GLE1):c.1089_1099del (p.Ala365fs)	Pathogenic
2002983	NM_001003722.2(GLE1):c.523_527del (p.Trp175fs)	Pathogenic
2003633	NM_001003722.2(GLE1):c.1951dup (p.Asp651fs)	Pathogenic
2014590	NC_000009.12:g.128525190AG[1]	Pathogenic
2023936	NM_001003722.2(GLE1):c.724C>T (p.Gln242Ter)	Pathogenic
2027636	NM_001003722.2(GLE1):c.1267C>T (p.Gln423Ter)	Pathogenic
2040335	NM_001003722.2(GLE1):c.1925G>A (p.Trp642Ter)	Pathogenic
2049962	NM_001003722.2(GLE1):c.2028+2T>C	Pathogenic
2073222	NM_001003722.2(GLE1):c.853C>T (p.Gln285Ter)	Pathogenic

SpliceAI

1840 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128515528:G:T	acceptor_loss	1.0000
9:128515635:GAACA:G	donor_gain	1.0000
9:128515637:ACA:A	donor_gain	1.0000
9:128515640:G:GG	donor_gain	1.0000
9:128515641:T:A	donor_loss	1.0000
9:128522814:GAG:G	donor_gain	1.0000
9:128523842:CAGAG:C	donor_loss	1.0000
9:128523844:GAG:G	donor_gain	1.0000
9:128523845:AGGTG:A	donor_loss	1.0000
9:128523846:GGTGA:G	donor_loss	1.0000
9:128523848:T:G	donor_loss	1.0000
9:128525186:T:TA	acceptor_gain	1.0000
9:128525190:A:AG	acceptor_gain	1.0000
9:128525191:G:GG	acceptor_gain	1.0000
9:128525191:GA:G	acceptor_gain	1.0000
9:128525191:GAGCA:G	acceptor_gain	1.0000
9:128527177:A:AG	acceptor_gain	1.0000
9:128527178:G:GC	acceptor_gain	1.0000
9:128527178:GA:G	acceptor_gain	1.0000
9:128527178:GAC:G	acceptor_gain	1.0000
9:128527178:GACC:G	acceptor_gain	1.0000
9:128527178:GACCT:G	acceptor_gain	1.0000
9:128527287:GTCAG:G	donor_gain	1.0000
9:128527289:CAGGT:C	donor_loss	1.0000
9:128527290:AGG:A	donor_loss	1.0000
9:128527291:GG:G	donor_loss	1.0000
9:128527293:T:A	donor_loss	1.0000
9:128527501:G:GG	donor_gain	1.0000
9:128527537:GGGT:G	donor_gain	1.0000
9:128536352:TA:T	acceptor_loss	1.0000

AlphaMissense

4582 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:128538013:T:A	W602R	0.998
9:128538013:T:C	W602R	0.998
9:128538019:T:A	W604R	0.998
9:128538019:T:C	W604R	0.998
9:128527502:T:A	V430E	0.997
9:128533813:C:A	A503E	0.997
9:128536422:G:T	G572W	0.997
9:128536423:G:A	G572E	0.997
9:128536441:C:A	A578D	0.997
9:128536444:C:A	A579D	0.997
9:128533876:T:C	L524P	0.996
9:128536414:G:C	R569P	0.996
9:128536443:G:C	A579P	0.996
9:128527478:T:C	L422P	0.995
9:128533639:T:C	L480P	0.995
9:128533767:G:C	G488R	0.995
9:128533780:T:A	V492E	0.995
9:128533801:C:A	A499E	0.995
9:128533887:T:C	C528R	0.995
9:128536404:T:C	F566L	0.995
9:128536406:T:A	F566L	0.995
9:128536406:T:G	F566L	0.995
9:128536422:G:A	G572R	0.995
9:128536422:G:C	G572R	0.995
9:128536432:G:C	R575P	0.995
9:128539632:T:C	L633P	0.995
9:128527490:C:A	A426D	0.994
9:128533768:G:A	G488D	0.994
9:128536435:T:C	L576P	0.994
9:128538086:T:C	L626P	0.994

dbSNP variants (sampled 300 via entrez): RS1000018377 (9:128511375 G>A), RS1000085560 (9:128522716 C>G,T), RS1000125853 (9:128542479 C>G), RS1000164471 (9:128517062 G>A), RS1000247406 (9:128536731 G>C,T), RS1000306035 (9:128522660 CT>C), RS1000360168 (9:128536362 G>C), RS1000507039 (9:128536845 A>C), RS1000536195 (9:128517448 A>G), RS1000539196 (9:128536569 T>C), RS1000567683 (9:128528504 C>A,G,T), RS1000634471 (9:128529875 C>G), RS1000694613 (9:128534900 A>G), RS1000954448 (9:128512672 CTT>C,CT,CTTT), RS1001002127 (9:128527872 G>T)

Disease associations

OMIM: gene MIM:603371 | disease phenotypes: MIM:253310, MIM:611890

GenCC curated gene-disease

Disease	Classification	Inheritance
lethal arthrogryposis-anterior horn cell disease syndrome	Definitive	Autosomal recessive
lethal congenital contracture syndrome 1	Strong	Autosomal recessive
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Limited	AD

Mondo (3): lethal congenital contracture syndrome 1 (MONDO:0009670), lethal arthrogryposis-anterior horn cell disease syndrome (MONDO:0012750), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (3): Lethal congenital contracture syndrome type 1 (Orphanet:1486), Arthrogryposis-anterior horn cell disease syndrome (Orphanet:53696), Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000217	Xerostomia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000545	Myopia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000765	Abnormal thorax morphology
HP:0000772	Abnormal rib morphology
HP:0000954	Single transverse palmar crease
HP:0000969	Edema
HP:0001188	Hand clenching
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002115_14	Axial length	6.000000e-06
GCST005951_65	Body mass index	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:0004340	body mass index

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C567502	Lethal Arthrogryposis With Anterior Horn Cell Disease (supp.)
C537194	Lethal congenital contracture syndrome 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases methylation	1
kojic acid	decreases expression	1
sodium arsenite	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Silicon Dioxide	decreases methylation	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS