These Vdr knockout mutants exhibit a phenotype similar to that seen in patients with hereditary vitamin D-dependent rickets type II. They display a range of traits including hypocalcemia, hypophosphatemia, hyperparathyroidism, increased serum parathyroid hormone, abnormal blood mineral levels, and growth retardation.
Marie Demay, Massachusetts General Hospital
Heterozygous mice are phenotypically indistinguishable from wildtype siblings. As originally characterized on a mixed B6;129 genetic background, homozygous mice are viable and fertile with normal survival until approximately 14 months. RNA isolated from the intestine and kidney show a truncated deletion of the second zinc finger coding region followed by a premature termination codon, resulting in the absence of receptor protein. Homozygous mice exhibit an identical phenotype as the human disease hereditary vitamin D-dependent rickets type II (HVDDR). As early as 21 days of age, mutant mice demonstrate hypocalcemia, hypophosphatemia, hyperparathyroidism, increased serum parathyroid hormone, abnormal blood mineral levels, and growth retardation. In addition, renin and plasma angiotensin II levels are increased. Homozygous mice are hypertensive and exhibit cardiachypertrophy. At 4 weeks of age, homozygous mice exhibit perioral and periorbital alopecia that progresses over the entire body by 4 months of age. Rickets and osteomalacia develop by 35 days. Homozygous mice have increased bone fragility and other skeletal abnormalities. Introducing a diet enriched for calcium, phosphorus, and lactose, to young homozygous mice prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia. Lymphocytes isolated from homozygous mice have an inflammatory phenotype. Null mice have increased susceptibility to induced inflammatory bowel disease. Mutant mice may be useful in studies of rickets, alopecia, skeletal homeostasis, intestinal absorption, and inflammatory bowel disease.
( Note: It has been the experience of The Jackson Laboratory that homozygotes on the C57BL/6 congenic background survive to only 2 months of age.)
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
A targeting vector containing a mouse phosphoglycerate kinase promoter driven neomycin resistance gene was used to replace exon 3 of the endogenous gene. The construct was electroporated into the 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric mice were bred to C57BL/6 to generate mutant colonies. The donating investigator stated that heterozygotes were mated to C57BL/6 mice (see SNP note below) for more than 8 generations before arriving at The Jackson Laboratory.
A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, at least 1 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.
|Allele Name||targeted mutation 1, Marie B Demay|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||VDR -; VDR-KO; VDRKO|
|Gene Symbol and Name||Vdr, vitamin D (1,25-dihydroxyvitamin D3) receptor|
|Gene Synonym(s)||NR1I1; Nr1i1; PPP1R163|
|Strain of Origin||129S4/SvJae|
|Molecular Note||A 5 kb region of the gene encompassing exon 3 was replaced with a PGK-neo cassette via homologous recombination resulting in deletion of the second zinc finger of the DNA-binding domain. RT-PCR analysis of intestines and kidneys from homozygous mutant animals detected a mutant transcript. Sequence analysis revealed a 131 bp deletion corresponding to the second zinc finger and results in a frameshift and nonsense codon 12 bp downstream.|
|Mutations Made By|| |
Marie Demay, Massachusetts General Hospital
When maintaining a live colony on a C57BL/6 background, mutant mice can be bred as heterozygotes.
|Please inquire about possible genotypes.|
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