title: Mice deficient for cytosolic thymidine kinase gene develop fatal kidney disease.
abstract: The thymidine kinase (Tk) gene codes for a cytosolic protein involved in the pyrimidine nucleotide salvage pathway. A functional Tk gene is not necessary for cells in culture, and a naturally occurring Tk deficient phenotype has not been described in humans or animal models. In order to determine the biological significance of the Tk gene, we created Tk(-/-) knockout (KO) mice through homologous recombination in mouse embryonic stem cells. Tk KO mice have shortened life spans compared with their wild-type or Tk heterozygous (HET) siblings. All Tk KO mice develop sclerosis of kidney glomeruli and die before one year of age of kidney failure. Among other changes in KO animals, the most consistent is a switch from exclusively mucous secretion to predominantly serous secretion in the sublingual salivary gland. HET parents can produce KO mice at a frequency approaching Mendelian inheritance. Other observations in KO animals include an elevated level of serum thymidine, a significant decrease in the cloning efficiency of splenic lymphocytes, an increase in the frequency of hypoxanthine guanine phosphoribosyl transferase gene mutant lymphocytes, and histological alteration in the lymphoid structure of the spleen. In addition, KO animals sporadically exhibit inflammation of the arteries, which taken together with the lymphocyte and spleen abnormalities, suggest an abnormal immune system. Alterations in Tk KO mice indicate that the pyrimidine nucleotide salvage pathway is indispensable in vivo.
authors.affiliation: National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA. vdobrovolsky@nctr.fda.gov
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Dobrovolsky
authors.forename: Thomas
authors.initials: T
authors.lastname: Bucci
authors.forename: Robert H
authors.initials: RH
authors.lastname: Heflich
authors.forename: John
authors.initials: J
authors.lastname: Desjardins
authors.forename: Frank C
authors.initials: FC
authors.lastname: Richardson
mesh_terms: D000818:Animals; D001167:Arteritis / Q000473:pathology; D001947:Breeding; D003600:Cytosol / Q000201:enzymology; D005260:Female; D005838:Genotype; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007674:Kidney Diseases / Q000201:enzymology* / Q000473:pathology; D008136:Longevity; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D012737:Sex Factors; D013154:Spleen / Q000473:pathology; D013936:Thymidine / Q000097:blood; D013937:Thymidine Kinase / Q000172:deficiency* / Q000235:genetics
chemical_list: D007041:Hypoxanthine Phosphoribosyltransferase; D013937:Thymidine Kinase; D013936:Thymidine