RGD Reference Report - Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions. - Rat Genome Database

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Generation of novel genetically modified rats to reveal the molecular mechanisms of vitamin D actions.

Authors: Nishikawa, Miyu  Yasuda, Kaori  Takamatsu, Masashi  Abe, Keisuke  Okamoto, Kairi  Horibe, Kyohei  Mano, Hiroki  Nakagawa, Kimie  Tsugawa, Naoko  Hirota, Yoshihisa  Horie, Tetsuhiro  Hinoi, Eiichi  Okano, Toshio  Ikushiro, Shinichi  Sakaki, Toshiyuki 
Citation: Nishikawa M, etal., Sci Rep. 2020 Mar 30;10(1):5677. doi: 10.1038/s41598-020-62048-1.
RGD ID: 32716373
Pubmed: PMID:32231239   (View Abstract at PubMed)
PMCID: PMC7105495   (View Article at PubMed Central)
DOI: DOI:10.1038/s41598-020-62048-1   (Journal Full-text)

Recent studies have suggested that vitamin D activities involve vitamin D receptor (VDR)-dependent and VDR-independent effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 25-hydroxyvitamin D3 (25(OH)D3) and ligand-independent effects of the VDR. Here, we describe a novel in vivo system using genetically modified rats deficient in the Cyp27b1 or Vdr genes. Type II rickets model rats with a mutant Vdr (R270L), which recognizes 1,25(OH)2D3 with an affinity equivalent to that for 25(OH)D3, were also generated. Although Cyp27b1-knockout (KO), Vdr-KO, and Vdr (R270L) rats each showed rickets symptoms, including abnormal bone formation, they were significantly different from each other. Administration of 25(OH)D3 reversed rickets symptoms in Cyp27b1-KO and Vdr (R270L) rats. Interestingly, 1,25(OH)2D3 was synthesized in Cyp27b1-KO rats, probably by Cyp27a1. In contrast, the effects of 25(OH)D3 on Vdr (R270L) rats strongly suggested a direct action of 25(OH)D3 via VDR-genomic pathways. These results convincingly suggest the usefulness of our in vivo system.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal cartilage morphology  IMP 32716373; 32716373; 32716373; 32716373; 32716373; 32716373; 32716373; 32716373 RGD 
abnormal femur morphology treatmentIMPvitamin D332716373; 32716373; 32716373compared to Jcl:Wi and untreatedRGD 
abnormal femur morphology  IMP 32716373; 32716373; 32716373 RGD 
abnormal skin appearance  IMP 32716373; 32716373; 32716373 RGD 
abnormal survival  IMP 32716373; 32716373compared to CE-2 diet containing 1.15% calcium fed Cyp27b1-KO ratsRGD 
abnormal survival penetranceIMPcontrolled content diet32716373compared to CE-2 diet containing 1.15% calcium fed Cyp27b1-KO ratsRGD 
abnormal trabecular bone morphology  IMP 32716373; 32716373; 32716373; 32716373; 32716373 RGD 
alopecia  IMP 32716373; 32716373; 32716373 RGD 
decreased body height  IMP 32716373; 32716373; 32716373 RGD 
decreased circulating calcium level treatmentIMPvitamin D332716373; 32716373; 32716373; 32716373; 32716373; 32716373compared to Jcl:Wi and untreatedRGD 
increased body weight treatmentIMPvitamin D332716373; 32716373compared to untreatedRGD 
increased body weight treatmentIMPvitamin D332716373compared to untreatedRGD 
increased bone mineral density of femur treatmentIMPvitamin D332716373; 32716373; 32716373compared to Jcl:Wi and untreatedRGD 
increased circulating parathyroid hormone level treatmentIMPvitamin D332716373; 32716373; 32716373; 32716373; 32716373; 32716373compared to Jcl:Wi and treatedRGD 
increased circulating parathyroid hormone level  IMPvitamin D332716373; 32716373; 32716373 RGD 
nephrolithiasis  IMP 32716373; 32716373; 32716373 RGD 
osteomalacia treatmentIMPvitamin D332716373; 32716373; 32716373compared to Jcl:Wi and treatedRGD 
osteomalacia  IMP 32716373; 32716373; 32716373 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Cyp27b1  (cytochrome P450, family 27, subfamily b, polypeptide 1)
Cyp27b1em1Thka  (cytochrome P450, family 27, subfamily b, polypeptide 1; CRISPR/Cas9 induced mutant 1, Thka)
Vdr  (vitamin D receptor)
Vdrem1Thka  (vitamin D receptor; CRISPR/Cas9 induced mutant 1, Thka)
Vdrem2Thka  (vitamin D receptor; CRISPR/Cas9 induced mutant 2, Thka)

Genes (Mus musculus)
Cyp27b1  (cytochrome P450, family 27, subfamily b, polypeptide 1)
Vdr  (vitamin D (1,25-dihydroxyvitamin D3) receptor)

Genes (Homo sapiens)
CYP27B1  (cytochrome P450 family 27 subfamily B member 1)
VDR  (vitamin D receptor)


Additional Information