LOXL3
protein-codinglysyl oxidase like 3, the group of Scavenger receptor cysteine rich domain containing
Gene summary
This gene encodes a lysyl oxidase, which likely functions as an amine oxidase and plays a role in the formation of crosslinks in collagens and elastin. Deletion of the related gene in mouse causes neonatal mortality with cleft palate, spine deformity, and defects in collagen organization. A mutation in this gene was found in a family with Stickler syndrome. [provided by RefSeq, Sep 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019354
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0019354
Submitter: Ambry Genetics
Inheritance Pattern: Unknown
Disease ID:MONDO:0030697
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030697
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0016647
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019354
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0030697
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LOXL3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_032603.5. 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 | 6 | 151 | 1 | 158 | ||
| missense | 1 | 1 | 240 | 13 | 255 | |
| nonsense | 1 | 10 | 11 | |||
| start loss | 0 | |||||
| frameshift | 1 | 3 | 9 | 13 | ||
| splice donor/acceptor (+/-2bp) | 1 | 6 | 7 | |||
| Total | 2 | 6 | 271 | 164 | 1 | 444 |
Highest pathogenic variant AF is 0.0006683622
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_115992.1 | 13 | MANE Select | |
| Ensembl | ENSP00000264094.3 | 13 | MANE Select | |
| RefSeq | NP_001276093.1 | 11 | Standard | |
| RefSeq | NP_001276094.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| loxl3b | Danio rerio | Structure: ceratobranchial cartilage Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- TYROBP Causal Network
- Crosslinking of collagen fibrils
- Assembly of collagen fibrils and other multimeric structures
- Collagen formation
- Extracellular matrix organization
Biological Process
- epithelial to mesenchymal transition
- receptor-mediated endocytosis
- inflammatory response
- peptidyl-lysine oxidation
- spinal cord development
Molecular Function
- fibronectin binding
- protein-lysine 6-oxidase activity
- scavenger receptor activity
- copper ion binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- cytoplasm
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000264094
- Coding exons
- 13
- Length
- 23277
- Individuals with no LoFs
- 125635
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 113
- Defined
- 125748
- p
- 0.000449
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.56 | 375 | 471 | 0.797 | 0.0000282 | 4898 |
| Missense (PolyPhen) | 162 | 222.65 | 0.72759 | 2303 | ||
| Synonymous | 1.53 | 159 | 185 | 0.857 | 0.0000110 | 1503 |
| Loss of Function | 2.29 | 27 | 43.3 | 0.624 | 0.00000244 | 403 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00063 | 0.00062 | rare |
| Latino/Admixed American | 0.00050 | 0.00049 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0.00087 | 0.00082 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00055 | 0.00055 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins (PubMed:17018530, PubMed:28065600). Catalyzes the post- translational oxidative deamination of peptidyl lysine residues in precursors of elastin and different types of collagens, a prerequisite in the formation of cross-links between collagens and elastin (PubMed:17018530). Required for somite boundary formation by catalyzing oxidation of fibronectin (FN1), enhancing integrin signaling in myofibers and their adhesion to the myotendinous junction (MTJ) (By similarity). Acts as a regulator of inflammatory response by inhibiting differentiation of naive CD4(+) T-cells into T-helper Th17 or regulatory T-cells (Treg): acts by interacting with STAT3 in the nucleus and catalyzing both deacetylation and oxidation of lysine residues on STAT3, leading to disrupt STAT3 dimerization and inhibit STAT3 transcription activity (PubMed:28065600). Oxidation of lysine residues to allysine on STAT3 preferentially takes place on lysine residues that are acetylated (PubMed:28065600). Also able to catalyze deacetylation of lysine residues on STAT3 (PubMed:28065600). {ECO:0000250|UniProtKB:Q9Z175, ECO:0000269|PubMed:17018530, ECO:0000269|PubMed:28065600}.; FUNCTION: Isoform 2: Shows protein-lysine 6-oxidase activity toward elastin and different types of collagens, with the highest activity toward collagen type IV (PubMed:17018530). {ECO:0000269|PubMed:17018530}.;
- Disease
- DISEASE: Note=Defects in LOXL3 are found in a family with an autosomal recessive form of Stickler syndrome, an inherited disorder that associates ocular signs with more or less complete forms of Pierre Robin sequence and sensorineural deafness (PubMed:25663169). Pierre Robin sequence includes an opening in the roof of the mouth (a cleft palate) (PubMed:25663169). The degree of hearing loss varies among affected individuals and may become more severe over time (PubMed:25663169). Syndrome expressivity is variable (PubMed:25663169). Ocular disorders include non-progressive myopia with associated chorioretinal degeneration (PubMed:25663169). Defects in LOXL3 are found in another family with early-onset high myopia (PubMed:26957899). The disease may be caused by mutations affecting the gene represented in this entry (PubMed:25663169, PubMed:26957899). {ECO:0000269|PubMed:25663169, ECO:0000269|PubMed:26957899}.;
Recessive Scores
- pRec
- 0.161
Intolerance Scores
- LoFtool
- 0.897
- RVIS EVS
- 0
- RVIS percentile EVS
- 54.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.340
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |