Mice homozygous for this knock-out mutation exhibit dysmorphic features, alopecia, growth retardation, and skeletal defects.
Dr. Chantal Mathieu, LEGENDO
Heterozygous mice are viable, fertile, and phenotypically indistinguishable from wildtype siblings. Homozygous mutant mice are viable but infertile. No VDR mRNA is detected by RT-PCR in samples from the intestine or kidney or from homozygous mutant embryo. Increased expression of CTP27B1 and reduced expression of CYP24A1 and calbindin-D9k is detected by RT-PCR in samples from VDR-deficient kidneys.
Although mice homozygous for this targeted mutation are viable, shortly after weaning they exhibit dysmorphic features including a flat face and short nose, alopecia, growth retardation, and skeletal defects including hypocalcaemia, decreased bone mineral density, widened growth plates with hypomineralization, less trabeculae and thicker osteo seams. Homozygous mutant mice exhibit metabolic imbalances including abnormally high and low levels of 1,25(OH),2D3 and 25(OH)D3, respectively and abnormal cytokine and chemokine profiles.
Homozygous mice exhibit normal pancreatic islet architecture and insulitis severity is similar to NOD wildtype controls. Diabetes onset and incidence in mutant and wildtype mice is similar for both males (mutants 30% vs wildtypes 38%) and females (mutants 69% versus wildtype 70%) by 250 days of age.
Mice homozygous for this mutation may be useful in studies of rickets, alopecia, skeletal homeostasis, intestinal absorption, the role of 1,25(OH),2D3 in the immune system as it relates to T1D protection, and to determine the function of vitamin D3 analogs in pancreatic beta cells.
Vitamin D receptor, Vdr, is located on Chr 15, 97682461-97736330 bp. Vit. D deficiency in humans increases the risk for type I diabetes in genetically predisposed individuals. In the targeting construct, a neomycin cassette replaced a 1.1-kb fragment containing exon 2, which encodes the first of two zinc fingers in the DNA-binding domain. Properly targeted TT2, (C57BL/6 x CBA)F1, ES cell clones were introduced into CD-1 embryos. Mice carrying this mutation were backcrossed for 14 generation to NOD/Leuven prior to sibling mating. Microsatellite analysis confirms Idd alleles 1 through 15 are NOD in origin. In addition, a concentration of Mit markers were tested on Chr 15 to ensure NOD homozygosity because there are several immune and regulatory genes in close proximity to the Vdr gene. In 2007, the T1DR received this strain at generation N14F7 and mated with NOD/ShiLtJ (Stock No. 001976) once prior to sibling mating.
|Allele Name||targeted mutation 1, Shigeaki Kato|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||Tokyo VDR-KO; VDR KO; VDR-; VDRKO; Vdr KO|
|Gene Symbol and Name||Vdr, vitamin D (1,25-dihydroxyvitamin D3) receptor|
|Gene Synonym(s)||NR1I1; Nr1i1; PPP1R163|
|Strain of Origin||(C57BL/6NCrlj x CBA/JNCrlj)F1|
|Molecular Note||A neomycin resistance cassette replaced 1.1kb of sequence containing exon 2, which encodes the first zinc finger of the DNA binding domain. RT-PCR and Western blot analysis of intestinal tissue from homozygous mice detected the presence of a truncated transcript and protein that appears to use Met 53 in exon 3 as an initiation site. This truncated protein is able to bind ligand but lacks transactivation activity.|
|Mutations Made By|| |
Shigeaki Kato, The University of Tokyo, 113-0032
|Please inquire about possible genotypes.|
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