GeneBe

GLE1

protein-coding

GLE1 RNA export mediator, the group of Nucleoporins

Gene summary

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. [provided by RefSeq, Jul 2008]

Previous symbols:
  • GLE1L
  • LCCS1

MANE transcript

NM_001003722.2

Inheritance

AR, AD

ClinVar variants

P:157U:144B:241

Top phenotype

Congenital arthrogryposis with anterior horn cell disease; Lethal congenital contracture syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr9:128,504,655-128,543,874

External References & Databases

Ensembl (ENSG00000119392)NCBI Gene (2733)OMIM (603371)HGNC:4315GenCCUniProt (Q53GS7)AlphaFoldClinVar (GLE1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~39.2 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lethal arthrogryposis-anterior horn cell disease syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012750

Submitter: G2P

lethal arthrogryposis-anterior horn cell disease syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012750

Submitter: Orphanet

lethal congenital contracture syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009670

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*GLE1* was first reported in relation to amyotrophic lateral sclerosis (ALS) in 2015 (Kaneb HM, et al., 2015, PMID: 25343993). *GLE1* regulates gene expression at multiple steps, including nuclear mRNA export, translation initiation, and translation termination. ALS-linked variants operate by altering the overall hGle1 levels and/or shifting the subcellular pools of its two isoforms, hGle1B versus hGle1A. At least 7 rare variants have been reported in relation to ALS (including splicing, missense, and nonsense variants) from 7 probands in 2 publications (PMIDs: 25343993, 34025336). Experimentally, this gene-disease relationship is supported by its function at the nuclear pore complex (PMID: 9618489) and in stress granule assembly/disassembly (PMID: 25694449), two process that have been linked to ALS. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. Of note, *GLE1* is also Congenital arthrogryposis with anterior horn cell disease (OMIM # 611890) and Lethal congenital contracture syndrome 1 (OMIM# 253310). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism, phenotype, and inheritance pattern for ALS and thus curated it separately from the additional disease entities.

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

lethal congenital contracture syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009670

Submitter: PanelApp Australia

lethal congenital contracture syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009670

Submitter: Orphanet

lethal congenital contracture syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009670

Submitter: Natera

Clinical Genomic Database (CGD)

Congenital arthrogryposis with anterior horn cell disease; Lethal congenital contracture syndrome 1AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 7966188; 7897624; 18204449; 30239721Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GLE1 variants in ClinVar

9 Conditions Cataloged
not providedTotal: 571
Lethal congenital contractural syndrome Finnish typeTotal: 103
Inborn genetic diseasesTotal: 80
Lethal arthrogryposis-anterior horn cell disease syndromeTotal: 75
Lethal congenital contracture syndrome 1Total: 57
GLE1-related disorderTotal: 28
not specifiedTotal: 19
Amyotrophic lateral sclerosisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001003722.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
226
clinvar
3
clinvar
 236
missense
2
clinvar
7
clinvar
133
clinvar
12
clinvar
 154
nonsense
20
clinvar
26
clinvar
1
clinvar
 47
start loss
2
clinvar
 2
frameshift
37
clinvar
30
clinvar
 67
splice donor/acceptor (+/-2bp)
4
clinvar
29
clinvar
3
clinvar
 36
Total63941442383542

Highest pathogenic variant AF is 0.0003611135

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001003722.2RefSeqNP_001003722.116MANE Select
ENST00000309971.9EnsemblENSP00000308622.516MANE Select
NM_001411013.1RefSeqNP_001397942.117Standard
NM_001499.2RefSeqNP_001490.114Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
gle1Danio rerio

Structure: motor neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • mRNA export from nucleus
  • regulation of translational initiation
  • regulation of translational termination
  • poly(A)+ mRNA export from nucleus

Molecular Function

  • inositol hexakisphosphate binding
  • protein binding
  • phospholipid binding
  • translation initiation factor binding
  • identical protein binding

Cellular Component

  • extracellular space
  • nuclear pore
  • nucleolus
  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000309971
Coding exons
16
Length
37589
Individuals with no LoFs
125674
Homozygous LoFs
0
Heterozygous LoFs
74
Defined
125748
p
0.000294
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8063353790.8840.00002154568
Missense (PolyPhen)88120.450.73061437
Synonymous0.8351281410.9100.000007381329
Loss of Function2.862343.30.5310.00000220479

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000180.00018rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish00.0absent
East Asian0.0000550.000054rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000310.00031rare
South Asian0.000720.00072rare
Other0.000820.00081rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
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). {ECO:0000269|PubMed:12668658, ECO:0000269|PubMed:16000379, ECO:0000269|PubMed:9618489}.;
Disease
DISEASE: 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. {ECO:0000269|PubMed:18204449}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lethal arthrogryposis with anterior horn cell disease (LAAHD) [MIM:611890]: A 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. {ECO:0000269|PubMed:18204449}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.102

Intolerance Scores

LoFtool
0.923
RVIS EVS
-0.09
RVIS percentile EVS
47.06

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.647

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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