Phänotypische und genotypische Charakterisierung der ENU-induzierten Mausmutante HST001 zur Verwendung für die nephrologische Forschung

Phenotypic and genotypic characterization of the ENU-induced mutant
mouse line HST001 for use in nephrological research A dominant
mutation was established in the line HST001 within the Munich ENU
mouse mutagenesis project. On the genetic background of the inbred
strain C3H heterozygous mutant mice showed a pathological increase
of the plasma urea concentration. The phenotypic characterization
of the mutant line included the measurement of body and organ
weights, food intake and a broad spectrum of clinical chemical and
hematological parameters as well as histological investigations of
inner organs. For those examinations heterozygous mutant mice were
mated to C3H mice and the offspring were divided in the two groups
of mutant and wildtype littermates according to the concentration
of plasma urea. The mutation showed complete phenotypic penetrance
in all generations examined. In addition the genomic localization
of the causative mutation was determined by linkage analysis. At
the age of 4 weeks the body weight of the mutant mice and the
wildtype mice showed no difference. After 6 weeks the mutant mice
grew more slowly leading to a significantly lower body weight
compared to the wildtype littermates. At the age of 26 weeks the
body weight of mutant mice was about 20% reduced as compared to
controls. Mutants also showed a reduction of the nose-rump-length
and the body fat content. Regarding the relative organ weights the
mutant mice showed significantly higher values for the spleen and
the brain. The clinical-chemical and hematological parameters were
determined in the animals at the age of 12, 18 and 24 weeks. The
mutant mice had significantly higher plasma concentrations of urea
and total protein as well as a higher activity of the alkaline
phosphatase. Beside that they showed lower plasma concentrations of
triglycerides and glucose and a lower activity of amylase than the
wildtype mice. The mutants showed increasing plasma urea levels
whereas the levels decreased in the controls. At the age of 24
weeks the mutants showed levels, which were two-fold higher than
those of the controls. The histopathological investigation of the
kidneys did not reveal any alterations, which could to explain the
pathological increase of the plasma urea concentration in the
mutant mice. However urea secretion via the kidneys was impaired,
since the mutants showed significantly lower urine urea levels
compared to the wildtype mice. The investigation of the
hematological parameters resulted in the occurrence of altered
values in the 18 und 24 weeks old mice. The mutant mice showed
reduced numbers 91 of erythrocytes as well as decreased values for
hemoglobin concentration, mean corpuscular volume and hematocrit.
The hitherto existing results of the linkage analysis of the
mutation in the genome using polymorphic microsatellite markers
showed that the mutation maps to chromosome 7. This result has to
be confirmed and specified by using additional markers and a larger
number of animals.