Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.
OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.
Chen
H
H
Millennium Pharmaceuticals, Incorporated, Cambridge, Massachusetts 02139, USA.
Charlat
O
O
Tartaglia
L A
LA
Woolf
E A
EA
Weng
X
X
Ellis
S J
SJ
Lakey
N D
ND
Culpepper
J
J
Moore
K J
KJ
Breitbart
R E
RE
Duyk
G M
GM
Tepper
R I
RI
Morgenstern
J P
JP
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020738:Leptin; D051379:Mice; D008815:Mice, Inbred Strains; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine / Q000235:genetics*; D054411:Receptors, Leptin; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D002352:Carrier Proteins; D017931:DNA Primers; D018076:DNA, Complementary; C515448:LEPR protein, human; D020738:Leptin; D011506:Proteins; D011956:Receptors, Cell Surface; D018121:Receptors, Cytokine; D054411:Receptors, Leptin; C515447:leptin receptor, mouse