LIFR
protein-codingLIF receptor subunit alpha, the group of MicroRNA protein coding host genes|Fibronectin type III domain containing|CD molecules
Gene summary
This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2018]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~133.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011108
Submitter: ClinGen
LIFR is located on chromosome 5 at 5p13.1 and encodes leukemia inhibitory factor receptor protein. LIFR was first reported in relation to autosomal recessive Stüve-Wiedemann syndrome in 2004 (Dagoneau et al., PMID 14740318). At least 28 unique variants (nonsense, frameshift, splicing, missense, gross deletions) have been reported in affected individuals, 22 of which are predicted to cause a loss of function of the protein, suggesting biallelic loss of function is the mechanism of disease for this gene. Variants in this gene have been reported in at least 22 probands in four publications (Dagoneau et al., 2004, PMID 14740318; Jung et al., 2010, PMID 20447141; Yeşil et al., 2014, PMID 24988918; Maddirevula et al., 2018, PMID 29620724). Additional genetic evidence is available in the literature; however, the maximum score for genetic evidence (12 pts) was reached. Further evidence supporting this gene-disease relationship includes functional alteration experiments and a LIFR-deficient mouse model, which recapitulates several features of the disease phenotype, including feeding difficulties, skeletal abnormalities, decreased bone volume and nervous system dysfunction (Dagoneau et al., 2004 PMID 14740318; Bellais et al., 2010 PMID 19603067; Ware et al., 1995 PMID 7789261). In summary, LIFR is definitively associated with autosomal recessive Stüve-Wiedemann syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 2Sept2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0800043
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0019719
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0031280
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0800043
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011108
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0800043
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0019719
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
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
Comments: Individuals can have temperature control anomalies and other manifestations of dysautonomia
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to LIFR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001127671.2. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 14 | 361 | 1 | 376 | ||
| missense | 5 | 366 | 15 | 4 | 390 | |
| nonsense | 26 | 27 | 1 | 54 | ||
| start loss | 0 | |||||
| frameshift | 52 | 30 | 3 | 85 | ||
| splice donor/acceptor (+/-2bp) | 40 | 40 | ||||
| Total | 78 | 102 | 384 | 376 | 5 | 945 |
Highest pathogenic variant AF is 0.000037181173
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001121143.1 | 19 | MANE Select | |
| Ensembl | ENSP00000398368.2 | 19 | MANE Select | |
| RefSeq | NP_001351226.1 | 19 | Standard | |
| RefSeq | NP_001351227.1 | 19 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| lifrb | Danio rerio | Structure: cranial nerve V Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Jak-STAT signaling pathway - Homo sapiens (human)
- Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human)
- Cytokine-cytokine receptor interaction - Homo sapiens (human)
- JAK-STAT-Core
- Physiological and Pathological Hypertrophy of the Heart
Biological Process
- regulation of cytokine-mediated signaling pathway
- cell surface receptor signaling pathway
- positive regulation of cell population proliferation
- cytokine-mediated signaling pathway
- response to cytokine
Molecular Function
- cytokine receptor activity
- ciliary neurotrophic factor receptor activity
- leukemia inhibitory factor receptor activity
- oncostatin-M receptor activity
- ciliary neurotrophic factor receptor binding
Cellular Component
- plasma membrane
- integral component of plasma membrane
- external side of plasma membrane
- receptor complex
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263409
- Coding exons
- 19
- Length
- 133392
- Individuals with no LoFs
- 125682
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 66
- Defined
- 125748
- p
- 0.000262
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.241 | 563 | 579 | 0.972 | 0.0000299 | 7201 |
| Missense (PolyPhen) | 134 | 166.46 | 0.80502 | 2106 | ||
| Synonymous | -0.214 | 201 | 197 | 1.02 | 0.0000105 | 2040 |
| Loss of Function | 3.40 | 31 | 59.3 | 0.523 | 0.00000319 | 706 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00080 | 0.00079 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00034 | 0.00033 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Signal-transducing molecule. May have a common pathway with IL6ST. The soluble form inhibits the biological activity of LIF by blocking its binding to receptors on target cells.;
- Disease
- DISEASE: Stueve-Wiedemann syndrome (STWS) [MIM:601559]: Severe autosomal recessive condition and belongs to the group of the bent-bone dysplasias. SWS is characterized by bowing of the lower limbs, with internal cortical thickening, wide metaphyses with abnormal trabecular pattern, and camptodactyly. Additional features include feeding and swallowing difficulties, as well as respiratory distress and hyperthermic episodes, which cause death in the first months of life. The rare survivors develop progressive scoliosis, spontaneous fractures, bowing of the lower limbs, with prominent joints and dysautonomia symptoms, including temperature instability, absent corneal and patellar reflexes, and smooth tongue. {ECO:0000269|PubMed:14740318}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving LIFR is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(5;8)(p13;q12) with PLAG1.;
Recessive Scores
- pRec
- 0.309
Intolerance Scores
- LoFtool
- 0.794
- RVIS EVS
- -0.13
- RVIS percentile EVS
- 44.09
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.981
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |