LOXL2
protein-codinglysyl oxidase like 2, the group of Scavenger receptor cysteine rich domain containing
Gene summary
This gene encodes a member of the lysyl oxidase gene family. The prototypic member of the family is essential to the biogenesis of connective tissue, encoding an extracellular copper-dependent amine oxidase that catalyses the first step in the formation of crosslinks in collagens and elastin. A highly conserved amino acid sequence at the C-terminus end appears to be sufficient for amine oxidase activity, suggesting that each family member may retain this function. The N-terminus is poorly conserved and may impart additional roles in developmental regulation, senescence, tumor suppression, cell growth control, and chemotaxis to each member of the family. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~128.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LOXL2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002318.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 2 | 7 | |||
| missense | 152 | 2 | 1 | 155 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 5 | 5 | ||||
| Total | 0 | 0 | 163 | 2 | 3 | 168 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002309.1 | 13 | MANE Select | |
| Ensembl | ENSP00000373783.3 | 13 | MANE Select | |
| Ensembl | ENSP00000430519.1 | 2 | Standard | |
| Ensembl | ENSP00000427826.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| loxl2a | Danio rerio | Structure: angiogenic sprout Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Canonical and Non-Canonical TGF-B signaling
- Crosslinking of collagen fibrils
- Assembly of collagen fibrils and other multimeric structures
- Collagen formation
- Extracellular matrix organization
Biological Process
- negative regulation of transcription by RNA polymerase II
- response to hypoxia
- epithelial to mesenchymal transition
- endothelial cell proliferation
- sprouting angiogenesis
Molecular Function
- protein-lysine 6-oxidase activity
- scavenger receptor activity
- copper ion binding
- calcium ion binding
- protein binding
Cellular Component
- chromatin
- basement membrane
- extracellular space
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000389131
- Coding exons
- 13
- Length
- 128140
- Individuals with no LoFs
- 125701
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 47
- Defined
- 125748
- p
- 0.000187
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.225 | 483 | 497 | 0.972 | 0.0000320 | 5108 |
| Missense (PolyPhen) | 189 | 213.98 | 0.88324 | 2086 | ||
| Synonymous | -0.218 | 213 | 209 | 1.02 | 0.0000153 | 1446 |
| Loss of Function | 3.34 | 18 | 41.1 | 0.438 | 0.00000209 | 429 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00066 | 0.00065 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00015 | 0.00015 | rare |
| South Asian | 0.00017 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine) (PubMed:27735137). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation (PubMed:27735137). Shows no activity against histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27' (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated (H3K4me2) (PubMed:27735137). Also mediates deamination of methylated TAF10, a member of the transcription factor IID (TFIID) complex, which induces release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription (PubMed:25959397). LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2 (By similarity). Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin CDH1, probably by mediating deamination of histone H3 (PubMed:16096638, PubMed:27735137, PubMed:24414204). During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription (PubMed:24239292). SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits (PubMed:24239292). Interacts with the endoplasmic reticulum protein HSPA5 which activates the IRE1-XBP1 pathway of the unfolded protein response, leading to expression of several transcription factors involved in EMT and subsequent EMT induction (PubMed:28332555). Involved in E-cadherin repression following hypoxia, a hallmark of EMT believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression (PubMed:20026874). When secreted into the extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:20306300). Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding (PubMed:21835952). Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation (By similarity). {ECO:0000250|UniProtKB:P58022, ECO:0000269|PubMed:16096638, ECO:0000269|PubMed:20026874, ECO:0000269|PubMed:20306300, ECO:0000269|PubMed:21835952, ECO:0000269|PubMed:24239292, ECO:0000269|PubMed:24414204, ECO:0000269|PubMed:25959397, ECO:0000269|PubMed:27735137}.;
Recessive Scores
- pRec
- 0.0999
Intolerance Scores
- LoFtool
- 0.770
- RVIS EVS
- -1.59
- RVIS percentile EVS
- 3.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.458
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |