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]
Figure 1. The giant mice (top) exhibit increased body weights compared to wild-type littermates (bottom).
Figure 2. Homozygous giant mice exhibit increased body weights compared to wild-type littermates. Scaled body weights are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
Figure 3.Homozygous giant mice exhibit hyperglycemia 30 minutes after glucose treatment. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
Figure 4.Homozygous giant mice exhibit increased IgE levels in the peripheral blood. IgE levels were measured by ELISA. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
Figure 5.Homozygous giant mice exhibit reduced killing of natural killer target cells. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.
The giant phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R4345, some of which showed increased body weights (Figure 1 & 2), increased blood glucose levels 30 minutes after glucose bolus (Figure 3), increased levels of IgE levels in the peripheral blood (Figure 4), and reduced killing of natural killer target cells (Figure 5) compared to wild-type mice.
Nature of Mutation
Figure 6.Linkage mapping of the increased body weight phenotype using a recessive model of inheritance. Manhattan plot shows -log10 P values (Y-axis) plotted against the chromosome positions of 41 mutations (X-axis) identified in the G1 male of pedigree R4345. Scaled body weight phenotype data are shown for single locus linkage analysis without consideration of G2 dam identity. Horizontal pink and red lines represent thresholds of P = 0.05, and the threshold for P = 0.05 after applying Bonferroni correction, respectively.
Whole exome HiSeq sequencing of the G1 grandsire identified 41 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Lepr: a G to A transition at base pair 101,765,152 (v38) on chromosome 4, or base pair 48,019 in the GenBank genomic region NC_000070 within the donor splice site on intron 8 of the Lepr gene. The strongest association was found with a recessive model of linkage to the body weight phenotype, wherein two variant homozygotes departed phenotypically from six homozygous reference mice and 15 heterozygous mice with a P value of 1.213 x 10-17 (Figure 6).
The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in skipping of the 291-nucleotide exon 8 (out of 19 total exons), resulting in an in-frame deletion of 97 amino acids beginning after amino acid 329 of the encoded protein.
The donor splice site of intron 8, which is destroyed by the giant mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Illustration of Mutations in
Gene & Protein
Figure 7. Domain of OB-Rb and structure of mouse leptin receptor isoforms. OB-Rb contains the longest intracellular domain, which is crucial for leptin signaling. OB-Ra, OB-Rc and OB-Rd have varying short cytoplasmic domains. All isoforms contain the Box 1 motif known to bind JAK kinases. OB-Re is a secreted isoform of the leptin receptor. Cytokine receptor homology module (CRH)2 is the main binding site for leptin. The immunoglobin-like (IG-like) and fibronectin type III (FNIII) domains are involved in OB-R activation. The role of CRH1 remains to be determined. Both CRH domains also contain a FNIII fold (see text). The giant mutation s a donor splice site mutation in intron 8 that is predicted to result in the in-frame deletion of exon 8. Exon 8 encodes amino acids 330-426, which encompasses the Ig-like fold domain. This image is interactive. Other mutations found in the Lepr gene are noted in red. Click on the mutations for more specific information.
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 7; (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 giant mutation is a donor splice site mutation in intron 8 that is predicted to result in the in-frame deletion of exon 8. Exon 8 encodes amino acids 330-426, which encompasses the Ig-like fold domain.
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 giant mice exhibit obesity. The phenotype of the giant mice indicates that the LepRgiant protein exhibits loss of function.