|Coordinate||101,815,201 bp (GRCm38)|
|Base Change||C ⇒ A (forward strand)|
|Gene Name||leptin receptor|
|Synonym(s)||obl, Leprb, Obr, obese-like, OB-RGRP, Modb1, leptin receptor gene-related protein, LEPROT|
|Chromosomal Location||101,717,404-101,815,352 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]
PHENOTYPE: Homozygous mutants are hyperphagic, low-activity, poorly cold-adapted, sterile and have enhanced fat conversion. They are obese, hyperinsulinemic and, on certain strains, severely hyperglycemic. Heterozygotes are normal but resistant to prolonged fasting. [provided by MGI curators]
|Amino Acid Change||Glutamine changed to Lysine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000037385] [ENSMUSP00000102534]|
AA Change: Q1141K
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Predicted Effect||probably benign|
|Meta Mutation Damage Score||0.3601|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.742; ML prob: 0.688; human score: 1.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-09-04 9:27 PM by Anne Murray|
|Record Created||2019-03-27 3:10 PM by Bruce Beutler|
The donner phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R6650, some of which showed increased body weights compared to wild-type littermates (Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 45 mutations. The body weight phenotype was linked to a mutation in Lepr: a C to A transversion at base pair 101,815,201 (v38) on chromosome 4, or base pair 98,068 in the GenBank genomic region NC_000070. Linkage was found with a recessive model of inheritance, wherein 12 variant homozygotes departed phenotypically from 38 homozygous reference mice and 47 heterozygous mice with a P value of 9.644 x 10-10 (Figure 2).
The mutation corresponds to residue 3,973 in the mRNA sequence NM_146146 within exon 19 of 19 total exons.
The mutated nucleotide is indicated in red. The mutation results in a glutamine to lysine substitution at position 1,141 (Q1141K) in the LEPR protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.000).
|Illustration of Mutations in
Gene & Protein
The Lepr or obr gene encodes an 1162 amino acid protein that is the receptor for leptin, a four-helical cytokine-like hormone produced primarily by adipocytes [Figure 3; (1;2)]. The leptin receptor is a member of the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT (signal transducer and activator of transcription) proteins (see domino for more information on STAT signaling). Six isoforms of the leptin receptor are generated by alternative splicing; each isoform, with the exception of a soluble isoform (OB-Re) are single-pass membrane-spanning proteins differing only in the sequences of their C-terminal intracellular domains. The extracellular portion of the human leptin receptor contains two CK domains that contain conserved cysteine-containing motifs (amino acids 62-178 and amino acids 428-535), four domains that contain a fibronectin type III (FNIII) fold (amino acids 235-327, 536-635, 636-731, and amino acids 732-841), and a domain that has an Ig-like fold (amino acids 328-427). The first CK domain and the first FNIII domain form the cytokine receptor homology module 1 (CRH1), while the second CK domain and remaining FNIII domains form the cytokine receptor homology module 2.
The donner mutation results in a glutamine to lysine substitution at position 1,141 (Q1141K); amino acid 1,141 is within an undefined region after Box 3 and the C-terminus.
Please see the record for Business_class for more information on Lepr.
Leptin, a systemic hormone, regulates multiple functions of the body including energy utilization and storage, various endocrine axes, bone metabolism, thermoregulation, angiogenesis, immunity and inflammation by binding to the long form of the leptin receptor (OB-Rb) and subsequent initiation of various signal transduction pathways [reviewed in (3-5)]. It is primarily produced by adipocytes in proportion to fat stores, but can also be produced by placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach, mammary epithelial cells, bone marrow, pituitary and liver (6). Humans and other animals deficient for leptin or its receptor, exhibit hyperphagia and low metabolism that results in obesity and insulin resistance [OMIM #614963; (2;7;8)]. Similar to other Lepr mouse models (see MGI for a list of Lepr alleles as well as the entry for Business_class), the donner mice exhibit obesity. The phenotype of the donner mice indicates loss of LEPR-associated function.
1) 94°C 2:00
The following sequence of 424 nucleotides is amplified (chromosome 4, + strand):
1 cctccgtcaa cagaagagag agtggtgtgc ttttgactgg tgaggcagga atcctgtgca
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Zhang, F., Basinski, M. B., Beals, J. M., Briggs, S. L., Churgay, L. M., Clawson, D. K., DiMarchi, R. D., Furman, T. C., Hale, J. E., Hsiung, H. M., Schoner, B. E., Smith, D. P., Zhang, X. Y., Wery, J. P., and Schevitz, R. W. (1997) Crystal Structure of the Obese Protein Leptin-E100. Nature. 387, 206-209.
2. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J. M. (1994) Positional Cloning of the Mouse Obese Gene and its Human Homologue. Nature. 372, 425-432.
3. Zhang, F., Chen, Y., Heiman, M., and Dimarchi, R. (2005) Leptin: Structure, Function and Biology. Vitam Horm. 71, 345-372.
4. Malendowicz, L. K., Rucinski, M., Belloni, A. S., Ziolkowska, A., and Nussdorfer, G. G. (2007) Leptin and the Regulation of the Hypothalamic-Pituitary-Adrenal Axis. Int Rev Cytol. 263, 63-102.
6. Margetic, S., Gazzola, C., Pegg, G. G., and Hill, R. A. (2002) Leptin: A Review of its Peripheral Actions and Interactions. Int J Obes Relat Metab Disord. 26, 1407-1433.
7. Chen, H., Charlat, O., Tartaglia, L. A., Woolf, E. A., Weng, X., Ellis, S. J., Lakey, N. D., Culpepper, J., Moore, K. J., Breitbart, R. E., Duyk, G. M., Tepper, R. I., and Morgenstern, J. P. (1996) Evidence that the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice. Cell. 84, 491-495.
8. Farooqi, I. S., Wangensteen, T., Collins, S., Kimber, W., Matarese, G., Keogh, J. M., Lank, E., Bottomley, B., Lopez-Fernandez, J., Ferraz-Amaro, I., Dattani, M. T., Ercan, O., Myhre, A. G., Retterstol, L., Stanhope, R., Edge, J. A., McKenzie, S., Lessan, N., Ghodsi, M., De, R.,V, Perna, F., Fontana, S., Barroso, I., Undlien, D. E., and O'Rahilly, S. (2007) Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor. N Engl J Med. 356, 237-247.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Zhao Zhang and Bruce Beutler|