HGNC Approved Gene Symbol: LIFR
Cytogenetic location: 5p13.1 Genomic coordinates (GRCh38): 5:38,474,668-38,608,403 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.1 | Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome | 601559 | Autosomal recessive | 3 |
Gearing et al. (1991) isolated a cDNA clone encoding the human LIF receptor by expression screening of a human placenta cDNA library. The LIFR gene encodes a 1,097-amino acid transmembrane protein that is composed of 6 different domains: 2 cytokine receptor homology domains (CRH1 and CRH2), 1 immunoglobulin-like domain, 1 type III fibronectin domain with 3 modules, 1 transmembrane domain, and 1 cytoplasmic domain.
Using flow cytometry, immunohistochemical analysis, and in situ hybridization, Kubota et al. (2008) demonstrated that mouse retinal endothelial cells expressed Lif (159540), whereas Lifr was expressed in surrounding cells, such as astrocytes.
The LIFR gene contains 20 exons (Tomida and Gotoh, 1996).
The LIF receptor (LIFR) is the low-affinity binding chain that, together with the high-affinity converter subunit gp130 (600694), forms a high-affinity receptor complex that mediates the action of leukemia-inhibitory factor (LIF). LIF is a polyfunctional cytokine that affects the differentiation, survival, and proliferation of a wide variety of cells in the adult and the embryo (Gearing et al., 1993). The high-affinity complex also binds a related cytokine, oncostatin M (OSM; 165095). Both LIFR and gp130 are members of a family of cytokine receptors that includes components of the receptors for the majority of hematopoietic cytokines and for cytokines that affect other systems, including the ciliary neurotrophic factor (CNTF; 118945), growth hormone (GH; 139250), and prolactin (PRL; 176760).
Bozec et al. (2008) demonstrated that the FOS-related protein FRA2 (601575) controls osteoclast survival and size. They observed that bones of Fra2-deficient newborn mice had giant osteoclasts, and signaling through LIF and its receptor LIFR was impaired. Similarly, newborn animals lacking Lif had giant osteoclasts, and Bozec et al. (2008) demonstrated that LIF is a direct transcriptional target of FRA2 and c-JUN (604641). Moreover, bones deficient in Fra2 and Lif were hypoxic and expressed increased levels of hypoxia-induced factor 1-alpha (HIF1A; 603348) and Bcl2 (151430). Overexpression of Bcl2 was sufficient to induce giant osteoclasts in vivo, whereas Fra2 and Lif affected Hif1a through transcriptional modulation of the Hif prolyl hydroxylase Phd2 (606425). This pathway is operative in the placenta, because specific inactivation of Fra2 in the embryo alone did not cause hypoxia or the giant osteoclast phenotype. Bozec et al. (2008) concluded that thus, placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups.
Using somatic cell hybrid analysis, Gearing et al. (1993) demonstrated that the human LIFR gene is located on 5p13-p12. By interspecific backcross analysis, they showed that the murine locus is on chromosome 15 in a region of homology with human chromosome 5p. In both human and mouse genomes, the LIFR locus was linked to the genes encoding the receptors for interleukin-7 (IL7R; 146661), prolactin (PRLR; 176761), and growth hormone (GHR; 600946).
Stuve-Wiedemann syndrome-1 (STWS1; 601559) is a severe autosomal recessive disorder characterized by bowing of the long bones, with cortical thickening, flared metaphyses with coarsened trabecular pattern, camptodactyly, respiratory distress, feeding difficulties, and hyperthermic episodes responsible for early lethality. Clinical overlap with Schwartz-Jampel type 2 syndrome (SJS2) suggested that STWS and SJS2 could be allelic disorders; see 601559. Through studying a series of 19 families with STWS/SJS2, Dagoneau et al. (2004) mapped the disease gene to 5p13.1 at locus D5S418 and identified 14 distinct null mutations in the 19 families. An identical frameshift insertion (653_654insT; 151443.0001) was identified in families from the United Arab Emirates, suggesting founder effect. Twelve of the 14 mutations predicted premature termination of translation. Functional studies indicated that these mutations altered the stability of LIFR mRNA transcripts, resulting in the absence of the LIFR protein and the impairment of the JAK/STAT3 signaling pathway in patient cells. The authors concluded that STWS and SJS2 are indeed a single clinically and genetically homogeneous condition due to null mutations in the LIFR gene. Dagoneau et al. (2004) had considered LIFR to be a good candidate gene because, in addition to its map location, Lifr -/- mice present with reduction of fetal bone volume, with an increased volume of osteoclasts, reduction of astrocyte numbers in spinal cord and brain, and perinatal death (Ware et al., 1995).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human LIFR is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In 5 Omani and Yemeni families (families 15-19) originating from the United Arab Emirates, all with consanguineous parents, Dagoneau et al. (2004) found that children with Stuve-Wiedemann syndrome-1 (STWS1; 601559), also known as Schwartz-Jampel type 2 (SJS2), were homozygous for a 1-bp insertion, 653_654insT, in exon 6 of the LIFR gene causing frameshift and a stop 2 codons downstream.
In a family from Portugal (family 8), in 2 Gypsy families (families 6 and 7), and in 1 French family (family 9), Dagoneau et al. (2004) found that the STWS/SJS2 syndrome (STWS1; 601559) was associated with homozygosity for an arg597-to-stop (R597X) mutation in exon 13 of the LIFR gene. The same mutation was found in compound heterozygous state in 2 affected members of a Swiss family (family 12), the other mutation being a 1-bp insertion, 2011_2012insT (151443.0003), which resulted in frameshift and a stop 12 codons downstream.
For discussion of the 1-bp insertion in the LIFR gene (2011_2012insT) that was found in compound heterozygous state in patients with Stuve-Wiedemann syndrome (STWS1; 601559) by Dagoneau et al. (2004), see 151443.0002.
In a girl with Stuve-Wiedemann syndrome (STWS1; 601559), born of consanguineous Portuguese Gypsy parents, Gaspar et al. (2008) identified a homozygous 4-bp deletion (167_170delTAAC) in exon 3 of the LIFR gene, resulting in premature termination of translation 53 amino acids downstream.. The child was alive at age 12 years and showed typical signs of the disorder, including bowed limbs, facial dysmorphism, and later-onset dysautonomia. Gaspar et al. (2008) noted that survival past infancy is unusual in this disorder.
In 6 patients from 4 unrelated Turkish families with Stuve-Wiedemann syndrome (STWS1; 601559), Yesil et al. (2014) identified a homozygous c.2074C-T transition in exon 15 of the LIFR gene, resulting in an arg692-to-ter (R692X) substitution. Haplotype analysis suggested a founder effect.
In a 33-year-old woman with Stuve-Wiedemann syndrome (STWS1; 601559), Melone et al. (2014) identified a homozygous c.2170C-G transversion (c.2170C-G, NM_002310.5) in the LIFR gene, resulting in a pro724-to-ala (P724A) substitution at a conserved residue in the third fibronectin III motif. Genomewide SNP arrays, including parental samples, revealed a complete maternal isodisomy for chromosome 5; the mother carried the mutation in heterozygosity and no trace of paternal chromosome 5 was found from patient blood or skin biopsies. Transfection studies in Hep3B cells showed that the mutation caused abnormal receptor glycosylation and that the mutant receptor had decreased downstream activity compared to wildtype. The patient had most of the neonatal and subsequent features of the disorder, but did not have congenital dysplasia of the longs bones. In addition, she had very long survival and was pregnant at the time of report.
Bozec, A., Bakiri, L., Hoebertz, A., Eferl, R., Schilling, A. F., Komnenovic, V., Scheuch, H., Priemel, M., Stewart, C. L., Amling, M., Wagner, E. F. Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454: 221-225, 2008. [PubMed: 18548006] [Full Text: https://doi.org/10.1038/nature07019]
Dagoneau, N., Scheffer, D., Huber, C., Al-Gazali, L. I., Di Rocco, M., Godard, A., Martinovic, J., Raas-Rothschild, A., Sigaudy, S., Unger, S., Nicole, S., Fontaine, B., Taupin, J.-L., Moreau, J.-F., Superti-Furga, A., Le Merrer, M., Bonaventure, J., Munnich, A., Legeai-Mallet, L., Cormier-Daire, V. Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am. J. Hum. Genet. 74: 298-305, 2004. [PubMed: 14740318] [Full Text: https://doi.org/10.1086/381715]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Gaspar, I. M., Saldanha, T., Cabral, P., Vilhena, M. M., Tuna, M., Costa, C., Dagoneau, N., Cormier-Daire, V., Hennekam, R. C. M. Long-term follow-up in Stuve-Wiedemann syndrome: a clinical report. Am. J. Med. Genet. 146A: 1748-1753, 2008. [PubMed: 18546280] [Full Text: https://doi.org/10.1002/ajmg.a.32325]
Gearing, D. P., Druck, T., Huebner, K., Overhauser, J., Gilbert, D. J., Copeland, N. G., Jenkins, N. A. The leukemia inhibitory factor receptor (LIFR) gene is located within a cluster of cytokine receptor loci on mouse chromosome 15 and human chromosome 5p12-p13. Genomics 18: 148-150, 1993. [PubMed: 8276403] [Full Text: https://doi.org/10.1006/geno.1993.1441]
Gearing, D. P., Thut, C. J., VandenBos, T., Gimpel, S. D., Delaney, P. B., King, J., Price, V., Cosman, D., Beckmann, M. P. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 10: 2839-2848, 1991. [PubMed: 1915266] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07833.x]
Kubota, Y., Hirashima, M., Kishi, K., Stewart, C. L., Suda, T. Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice. J. Clin. Invest. 118: 2393-2403, 2008. [PubMed: 18521186] [Full Text: https://doi.org/10.1172/JCI34882]
Melone, M. A. B., Pellegrino, M. J., Nolano, M., Habecker, B. A., Johansson, S., Nathanson, N. M., Knappskog, P. M., Hahn, A. F., Boman, H. Unusual Stuve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy. Ann. Clin. Transl. Neurol. 1: 926-932, 2014. [PubMed: 25540807] [Full Text: https://doi.org/10.1002/acn3.126]
Tomida, M., Gotoh, O. Structure of the gene encoding the human differentiation-stimulating factor/leukemia inhibitory factor receptor. J. Biochem. 120: 201-205, 1996. [PubMed: 8864865] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021386]
Ware, C. B., Horowitz, M. C., Renshaw, B. R., Hunt, J. S., Liggitt, D., Koblar, S. A., Gliniak, B. C., McKenna, H. J., Papayannopoulou, T., Thoma, B., Cheng, L., Donovan, P. J., Peschon, J. J., Bartlett, P. F., Willis, C. R., Wright, B. D., Carpenter, M. K., Davison, B. L., Gearing, D. P. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121: 1283-1299, 1995. [PubMed: 7789261] [Full Text: https://doi.org/10.1242/dev.121.5.1283]
Yesil, G., Lebre, A. S., Dos Santos, S., Guran, O., Ozahi, I. I., Cormier-Daire, V., Guran, T. Stuve-Wiedemann syndrome: is it underrecognized? Am. J. Med. Genet. 164A: 2200-2205, 2014. [PubMed: 24988918] [Full Text: https://doi.org/10.1002/ajmg.a.36626]