| Description |
An intronic G-to-T transversion in this allele created a
donor splice site that causes abnormal splicing and the
inclusion of 106 nt of intronic sequence in the transcript,
leading to premature termination of the long cellular domain
of the Ob-Rb splice form and loss of its signal transducing
function. (J:31324, J:31327, J:31488)
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| Phenotype Description |
Mice homozygous for the diabetes spontaneous mutation
(Leprdb) become identifiably obese around 3 to 4 weeks of
age. Elevations of plasma insulin begin at 10 to 14 days and
of blood sugar at 4 to 8 weeks. Homozygous mutant mice are
polyphagic, polydipsic, and polyuric. The course of the
disease is markedly influenced by genetic background. A
number of features are observed on the C57BLKS background,
including an uncontrolled rise in blood sugar, severe
depletion of the insulin-producing beta-cells of the
pancreatic islets, and death by 10 months of age. Exogenous
insulin fails to control blood glucose levels and
gluconeogenic enzyme activity increases. Peripheral
neuropathy and myocardial disease are seen in C57BLKS Leprdb
homozygotes. Wound healing is delayed and metabolic
efficiency is increased. Although normal in body weight,
blood glucose, and plasma insulin, heterozygotes (Leprdb/+)
also have increased metabolic efficiency and can survive a
prolonged fast longer than controls. Experiments involving
destruction of the ventromedial nucleus of the hypothalamus
suggest that Leprdb may cause a defect in the hypothalamus.
Steroid sulfotransferase enzymes, aberrantly expressed in
diabetic mice, interact with the Leprdb mutation as
modifiers of gender difference s in obesity-induced diabetes
susceptibility.
The diabetes mutation is a result of a point mutation in the
leptin receptor gene, Lepr. This point mutation promotes
abnormal splicing, creating a stop codon that shortens the
intracellular domain of the receptor, such that its
signaling capacity is curtailed. The ligand, leptin, has
been shown to be a key weight control hormone that is
mutated in the mouse obesity mutation, Lepob. Morbid obesity
with hypogonadism is seen in patients with mutations in the
Leptin receptor gene, however the incidence is rare.
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