Phenotypic Mutation 'cherub' (pdf version)
Allelecherub
Mutation Type missense
Chromosome4
Coordinate101,625,259 bp (GRCm39)
Base Change T ⇒ A (forward strand)
Gene Lepr
Gene Name leptin receptor
Synonym(s) leptin receptor gene-related protein, obl, Obr, Leprb, obese-like, Modb1, LEPROT, OB-RGRP
Chromosomal Location 101,574,601-101,672,549 bp (+) (GRCm39)
MGI Phenotype 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]
Accession Number

NCBI RefSeq: NM_146146, NM_010704; MGI: 104993

MappedYes 
Amino Acid Change Proline changed to Threonine
Institutional SourceBeutler Lab
Gene Model not available
AlphaFold P48356
SMART Domains Protein: ENSMUSP00000037385
Gene: ENSMUSG00000057722
AA Change: P472T

DomainStartEndE-ValueType
transmembrane domain 7 29 N/A INTRINSIC
FN3 236 315 1.5e-5 SMART
Pfam:Lep_receptor_Ig 328 418 6.3e-23 PFAM
FN3 535 618 4.93e-1 SMART
FN3 641 721 3.25e1 SMART
FN3 736 818 2.35e0 SMART
transmembrane domain 838 860 N/A INTRINSIC
low complexity region 908 921 N/A INTRINSIC
low complexity region 1050 1065 N/A INTRINSIC
Predicted Effect probably benign

PolyPhen 2 Score 0.164 (Sensitivity: 0.92; Specificity: 0.87)
(Using ENSMUST00000037552)
SMART Domains Protein: ENSMUSP00000099838
Gene: ENSMUSG00000057722
AA Change: P472T

DomainStartEndE-ValueType
transmembrane domain 7 29 N/A INTRINSIC
FN3 236 315 1.5e-5 SMART
Pfam:Lep_receptor_Ig 329 420 2.6e-29 PFAM
FN3 535 618 4.93e-1 SMART
FN3 641 721 3.25e1 SMART
FN3 736 818 2.35e0 SMART
transmembrane domain 838 860 N/A INTRINSIC
Predicted Effect probably benign

PolyPhen 2 Score 0.044 (Sensitivity: 0.94; Specificity: 0.83)
(Using ENSMUST00000102777)
SMART Domains Protein: ENSMUSP00000102534
Gene: ENSMUSG00000057722
AA Change: P472T

DomainStartEndE-ValueType
transmembrane domain 7 29 N/A INTRINSIC
FN3 236 315 1.5e-5 SMART
Pfam:Lep_receptor_Ig 329 420 2.6e-29 PFAM
FN3 535 618 4.93e-1 SMART
FN3 641 721 3.25e1 SMART
FN3 736 818 2.35e0 SMART
transmembrane domain 838 860 N/A INTRINSIC
Predicted Effect probably benign

PolyPhen 2 Score 0.252 (Sensitivity: 0.91; Specificity: 0.88)
(Using ENSMUST00000106921)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Non Essential (E-score: 0.000) question?
Phenotypic Category Autosomal Semidominant
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance 100% 
Alleles Listed at MGI
All alleles(36) : Targeted, knock-out(3) Targeted, other(12) Transgenic(1) Spontaneous(13) Chemically induced(7)
Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00089:Lepr APN 4 101672232 missense probably benign
IGL01111:Lepr APN 4 101671852 missense possibly damaging 0.77
IGL01324:Lepr APN 4 101625265 missense probably benign 0.23
IGL01372:Lepr APN 4 101592774 missense possibly damaging 0.67
IGL01626:Lepr APN 4 101590731 missense probably benign 0.10
IGL01733:Lepr APN 4 101622279 missense probably benign 0.00
IGL01815:Lepr APN 4 101671987 missense possibly damaging 0.49
IGL01899:Lepr APN 4 101637184 missense possibly damaging 0.86
IGL02138:Lepr APN 4 101625264 missense probably damaging 0.98
IGL02161:Lepr APN 4 101602875 missense probably damaging 0.97
IGL02653:Lepr APN 4 101622141 missense probably benign 0.44
IGL02735:Lepr APN 4 101639835 missense probably damaging 1.00
IGL03035:Lepr APN 4 101622177 missense probably damaging 1.00
IGL03083:Lepr APN 4 101671876 nonsense probably null
IGL03160:Lepr APN 4 101622103 missense probably damaging 1.00
aufsetzigen UTSW 4 101609372 missense probably damaging 1.00
beastly UTSW 4 101671788 missense probably benign
business_class UTSW 4 101622069 missense probably damaging 1.00
clodhopper UTSW 4 101622487 splice site probably null
donner UTSW 4 101672398 missense probably damaging 1.00
fluffy UTSW 4 101649220 missense probably damaging 1.00
giant UTSW 4 101622349 critical splice donor site probably null
gordo UTSW 4 101622502 missense probably damaging 0.97
Immunoglutton UTSW 4 101622498 splice site probably benign
Jumbo_shrimp UTSW 4 101622151 nonsense probably null
lowleaning UTSW 4 101671588 splice site probably null
odd UTSW 4 101585271 splice site probably benign
paleo UTSW 4 101602842 missense possibly damaging 0.94
R0140_Lepr_245 UTSW 4 101625264 missense probably damaging 1.00
well-upholstered UTSW 4 101630155 synonymous probably benign
worldly UTSW 4 101625425 missense possibly damaging 0.96
PIT4651001:Lepr UTSW 4 101649194 missense probably damaging 1.00
PIT4696001:Lepr UTSW 4 101637180 missense probably benign 0.10
R0140:Lepr UTSW 4 101625264 missense probably damaging 1.00
R0197:Lepr UTSW 4 101609349 missense possibly damaging 0.64
R0279:Lepr UTSW 4 101607541 missense probably benign 0.05
R0487:Lepr UTSW 4 101625290 nonsense probably null
R0498:Lepr UTSW 4 101602889 missense probably benign 0.01
R0506:Lepr UTSW 4 101630207 splice site probably benign
R0512:Lepr UTSW 4 101671901 missense possibly damaging 0.87
R0512:Lepr UTSW 4 101649216 missense probably damaging 1.00
R0726:Lepr UTSW 4 101622131 missense probably benign 0.01
R1054:Lepr UTSW 4 101639793 missense probably damaging 0.97
R1109:Lepr UTSW 4 101628552 missense probably damaging 1.00
R1398:Lepr UTSW 4 101649216 missense probably damaging 1.00
R1464:Lepr UTSW 4 101592878 missense probably benign 0.08
R1464:Lepr UTSW 4 101592878 missense probably benign 0.08
R1519:Lepr UTSW 4 101646541 missense probably damaging 0.97
R1602:Lepr UTSW 4 101602842 missense possibly damaging 0.94
R1830:Lepr UTSW 4 101592874 missense probably damaging 1.00
R1850:Lepr UTSW 4 101590620 missense possibly damaging 0.67
R1918:Lepr UTSW 4 101630033 missense probably benign 0.08
R1928:Lepr UTSW 4 101639927 splice site probably benign
R2099:Lepr UTSW 4 101630185 missense probably damaging 1.00
R2102:Lepr UTSW 4 101630178 missense possibly damaging 0.95
R2175:Lepr UTSW 4 101622576 missense probably benign 0.01
R2254:Lepr UTSW 4 101672309 missense probably benign 0.26
R2396:Lepr UTSW 4 101590725 missense probably benign 0.19
R2508:Lepr UTSW 4 101648093 missense probably damaging 0.98
R2571:Lepr UTSW 4 101625369 missense possibly damaging 0.96
R3790:Lepr UTSW 4 101648111 splice site probably benign
R3882:Lepr UTSW 4 101672462 missense probably damaging 1.00
R3933:Lepr UTSW 4 101622498 splice site probably benign
R4211:Lepr UTSW 4 101590611 missense probably benign 0.19
R4343:Lepr UTSW 4 101622349 critical splice donor site probably null
R4345:Lepr UTSW 4 101622349 critical splice donor site probably null
R4544:Lepr UTSW 4 101625425 missense possibly damaging 0.96
R4546:Lepr UTSW 4 101671838 missense probably benign 0.35
R4724:Lepr UTSW 4 101622562 nonsense probably null
R4797:Lepr UTSW 4 101637244 missense possibly damaging 0.90
R4860:Lepr UTSW 4 101646534 missense probably benign 0.14
R4860:Lepr UTSW 4 101646534 missense probably benign 0.14
R4929:Lepr UTSW 4 101672314 missense probably benign 0.00
R4939:Lepr UTSW 4 101590635 missense possibly damaging 0.78
R5377:Lepr UTSW 4 101672216 missense possibly damaging 0.71
R5520:Lepr UTSW 4 101602734 missense probably benign 0.00
R5966:Lepr UTSW 4 101649324 intron probably benign
R6092:Lepr UTSW 4 101649220 missense probably damaging 1.00
R6130:Lepr UTSW 4 101622569 missense probably damaging 0.99
R6168:Lepr UTSW 4 101592789 missense probably damaging 0.99
R6232:Lepr UTSW 4 101671588 splice site probably null
R6380:Lepr UTSW 4 101622151 nonsense probably null
R6427:Lepr UTSW 4 101631454 missense possibly damaging 0.47
R6428:Lepr UTSW 4 101637295 missense probably damaging 1.00
R6641:Lepr UTSW 4 101622502 missense probably damaging 0.97
R6650:Lepr UTSW 4 101672398 missense probably damaging 1.00
R6859:Lepr UTSW 4 101622487 splice site probably null
R7023:Lepr UTSW 4 101646484 missense probably damaging 1.00
R7145:Lepr UTSW 4 101609394 missense probably benign 0.00
R7174:Lepr UTSW 4 101607535 missense probably benign 0.01
R7179:Lepr UTSW 4 101602856 missense probably benign 0.06
R7189:Lepr UTSW 4 101671961 missense probably benign 0.00
R7426:Lepr UTSW 4 101602853 missense probably benign 0.03
R7531:Lepr UTSW 4 101609372 missense probably damaging 1.00
R7620:Lepr UTSW 4 101609270 missense probably benign 0.41
R7804:Lepr UTSW 4 101639783 missense probably damaging 1.00
R8022:Lepr UTSW 4 101639754 missense probably benign 0.32
R8142:Lepr UTSW 4 101622616 missense possibly damaging 0.93
R8227:Lepr UTSW 4 101628559 missense probably damaging 0.99
R8426:Lepr UTSW 4 101671841 missense probably benign 0.12
R8447:Lepr UTSW 4 101671688 missense probably benign 0.08
R8531:Lepr UTSW 4 101622612 missense probably damaging 1.00
R8682:Lepr UTSW 4 101649269 missense probably benign 0.00
R8897:Lepr UTSW 4 101649233 missense probably damaging 0.98
R9096:Lepr UTSW 4 101631418 missense possibly damaging 0.95
R9177:Lepr UTSW 4 101602798 nonsense probably null
R9241:Lepr UTSW 4 101671788 missense probably benign
R9604:Lepr UTSW 4 101590473 missense probably benign 0.01
R9711:Lepr UTSW 4 101592851 nonsense probably null
X0026:Lepr UTSW 4 101590524 missense possibly damaging 0.47
Z1176:Lepr UTSW 4 101602811 missense probably damaging 0.99
Z1177:Lepr UTSW 4 101592792 missense probably damaging 1.00
Mode of Inheritance Autosomal Semidominant
Local Stock Sperm, gDNA
Repository

none

Last Updated 2019-03-30 7:44 AM by Diantha La Vine
Record Created unknown
Record Posted 2008-04-22
Phenotypic Description

The cherub mutation was identified in ENU-mutagenized G3 mice, and is characterized by massive obesity and infertility in homozygous animals (Figure 1).  The mutation mapped to Chromosome 4, and a mutation in the leptin receptor (Lepr) gene was found.  Cherub mutants have similar phenotypes to allelic Business class and Well-upholstered mutants.

Nature of Mutation
The cherub mutation was mapped to Chromosome 4 and corresponds to a T to A transversion at position 1413 (record for variant 1; NM_146146) of the Lepr transcript, in exon 9 of 18 total exons.
 
1396 AGGCGCAGCCTGTATTGTCCTGATAGTCCATCT
466  -R--R--S--L--Y--C--P--D--S--P--S-
 
The mutated nucleotide is indicated in red lettering and results in the conversion of cysteine 471 to a stop codon. This removes the C-terminal 691 amino acids of the leptin receptor (LEPR) protein.
Illustration of Mutations in
Gene & Protein
Protein Prediction
Figure 2. 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 cherub mutation causes a conversion of cysteine 471 to a stop codon. This image is interactive. Other mutations found in the Lepr gene are noted in red. Click on the mutations for more specific information. 
The cherub mutation results in protein truncation of the leptin receptor at amino acid 471. This deletes more than half of the protein including the C-terminal intracellular signaling domain, the membrane spanning region, and a significant portion of the extracellular region including a portion of the ligand-binding region (Figure 2).  It is unlikely that this truncated protein would have any function.
 
Please see the record for Business class for more information on Lepr.
Primers Primers cannot be located by automatic search.
Genotyping
Cherub genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide change.
 
Primers for PCR amplification
Cherub(F): 5’-GACCGACAACTCCTGACATGGAAG-3’
Cherub(R): 5’-GTGCTCTACAGAAATACCCAGTGGC-3’
 
PCR program
1) 94°C             2:00
2) 94°C             0:30
3) 56°C             0:30
4) 72°C             1:00
5) repeat steps (2-4) 29X
6) 72°C             7:00
7) 4°C               ∞
 
Primers for sequencing
Cherub_seq(F): same as Cherub(F)
Cherub_seq(R): 5’- ACCCAGTGGCTATGAATCTATTACC-3’
 
The following sequence of 1051 nucleotides (from Genbank genomic region NC_000070 for linear DNA sequence of Lepr) is amplified:
 
49998                   gac cgacaactcc tgacatggaa ggaaagcagg tttttgtttg
50041 tttgtttctt ttgtttttgc tttaaaccgt gtcttaaatt ccaacagaaa tggagaatgt
50101 aacaggcagt aatatttggc ttgactggca gggcttgaat actttctagt ccaaactgat
50161 ataatgaaaa caataccaaa tcctgatcct tacatgaatg cagttatggg ggtgggggtg
50221 gggtgagggt ggggggctca gcacagcatg aggagctgtg ttagggtcgc agcaatagga
50281 aggctgagaa ccttgttcta gggtaaccac cacagtcctg ctgctctgtg cctaacttac
50341 cttcttgcca gctcctcaca ccctcacacc catccttcac cagtcaccct ccacacagtg
50401 tttttatagt cactgtttgt ggaaagacta aaatccagct agagctcgga gctcaagaag
50461 gcctttctaa caacagcatc agtttttaga cagagaaaat gatctctgtc aaacaataaa
50521 tctgaattct agatgtcttt ttttttttaa atcaatacta catattaact ggctactttt
50581 aaaaaaatgt atatatatat cttttaaggc gcagcctgta ttgtcctgat agtccatcta
50641 ttcatcctac gtctgagccc aaaaactgcg tcttacagag agacggcttt tatgaatgtg
50701 ttttccagcc aatctttcta ttatctggct atacaatgtg gatcaggatc aaccattctt
50761 taggttcact tgactcgcca ccaacgtgtg tccttcctga ctccgtaggt acgtcagact
50821 atattatgta ttttccttat atacggctgt cattttctaa ttgcactata ttttgaagaa
50881 aaaaattgtt tctgtttata gagtaattga gaagatgatt ggctgtagaa gctttctagt
50941 tttgagattt ttattaccat tttgaattag ttttgatatt agtggtagca tgtttgttta
51001 taaatatagg taatagattc atagccactg ggtatttctg tagagcac
 
PCR primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is shown in red text.
Science Writers Nora G. Smart
Illustrators Diantha La Vine
AuthorsNengming Xiao, Bruce Beutler
Edit History
2011-07-06 3:39 PM (current)
2011-01-07 8:57 AM
2010-12-08 3:38 PM
2010-08-26 2:06 PM
2010-08-26 2:06 PM
2010-08-26 2:06 PM
2010-02-03 5:31 PM