DNA sequence analysis of hprt mutants persisting in peripheral blood of cynomolgus monkeys more than two years after ENU treatment

Harbach, P.R.; Mattano, S.S.; Zimmer, D.M.; Filipunas, A.L.; Wang, Y.; Aaron, C.S.

doi:10.1002/(sici)1098-2280(1999)33:1<42::aid-em5>3.3.co;2-g

Cited by 3 publications

(3 citation statements)

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“…Although ENU mutagenesis usually generates point mutations resulting in single base changes, insertion mutations have been reported previously. 17,18 In fact, one-or two-base insertion mutation occurred up to 37% in one series. 19 Both Western blotting (not shown) and immunofluorescence provided evidence that the sglt2 protein is not expressed in proximal tubules of Sweet Pee mutants.…”

Section: Discussionmentioning

confidence: 87%

The Sweet Pee Model for Sglt2 Mutation

Onay

Sison

et al. 2011

Journal of the American Society of Nephrology

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Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation. Here, we describe Sweet Pee, a mouse model that carries a nonsense mutation in the Slc5a2 gene, which results in the loss of sglt2 protein function. The phenotype of Sweet Pee mutants was remarkably similar to patients with mutations in the Scl5a2 gene. The Sweet Pee mutants had improved glucose tolerance, higher urinary excretion of calcium and magnesium, and growth retardation. Renal physiologic studies demonstrated a prominent distal osmotic diuresis without enhanced natriuresis. Sweet Pee mutants did not exhibit increased KIM-1 or NGAL, markers of acute tubular injury. After induction of diabetes, Sweet Pee mice had better overall glycemic control than wild-type control mice, but had a higher risk for infection and an increased mortality rate (70% in homozygous mutants versus 10% in controls at 20 weeks). In summary, the Sweet Pee model allows study of the long-term benefits and risks associated with inhibition of SGLT2 for the management of diabetes. Our model suggests that inhibiting SGLT2 may improve glucose control but may confer increased risks for infection, malnutrition, volume contraction, and mortality.

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Section: Discussionmentioning

confidence: 87%

The Sweet Pee Model for Sglt2 Mutation

Onay

Sison

et al. 2011

Journal of the American Society of Nephrology

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“…Almost all reported ENU-induced mutations are point mutations resulting in single base changes [8]. The insertional mutation identified here is rare but other insertions were identified in hprt mutants of ENU-treated monkey T cells [9].…”

Section: Identification Of Mutant Hlb382 and Genetic Mapping Studiesmentioning

confidence: 70%

An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Wang

Feng

et al. 2008

Biochemical and Biophysical Research Communications

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The TNF family is critical for development of lymphoid organs and plays significant roles in regulation of innate and adoptive immune responses. Here we describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutant strain, HLB382, with a point mutation in the Lta gene, which encodes lymphotoxin (LT) α, a member of the TNF family. Mutant mice had no lymph nodes and no Peyer's patches. Microscopically, the spleens had disordered follicles and no germinal centers or discernible marginal zones (MZ). While the development of T cells and follicular B cells was normal, the numbers of NK and MZ B cells were significantly reduced. Genomic DNA sequences revealed a single base pair insertion in the coding region of Lta resulting in a frame shift and a premature stop codon. This new strain provides opportunities for understanding the full range of Lta gene function on a pure C57BL/6 background.

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“…In cells with 0 6 -alkylguanine-DNA alkyltransferase, ENU-induced mutations are predominantly TA:AT (38-45%), with a very strong bias for T > A transversions on the non-transcribed strand [46,[50][51][52][53]. T > C and T > G mutations each make up ~ 15% of the mutations and G > A and C> T mutations each about 7%.…”

Section: Resultsmentioning

confidence: 99%

Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

Branda¹

2000

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and PERFORMING ORGANIZATION NAME{S) AND ADDRESS(ES)The University of Vermont Burlington, Vermont 05405-0160 E-MAIL:rbranda@zoo .uvm.edu The purpose of this research project is to understand better the effect of dietary folate levels on the cellular pharmacology and toxicology of chemotherapeutic agents. The scope of the research involves in vitro studies with cell lines and in vivo assessments in rats of folate-chemotherapeutic drug interactions. Studies at a molecular level led to a new model to explain the synergy between nutritional folate deficiency and alkylating agents. Our studies at a cellular level suggest that folate metabolism can modulate glutathione levels. This observation may explain at least in part why dietary folate levels influence the efficacy and toxicity of alkylating agents. Studies in rats confirm that dietary folate levels affect the toxicity of cyclophosphamide, but there may be an optimal amount of dietary folate to reduce that toxicity. These in vivo studies also indicate that other aspects of diet are important in determining sensitivity to chemotherapy. Rats maintained on a cereal-based diet were much more resistant to the toxic effects of cyclophosphamide than rats eating a Purified Diet. Taken together, our studies suggest that dietary changes can have a profound and largely unappreciated effect on the outcome of cancer chemotherapy. Where copyrighted material is quoted, permission has been obtained to use such material. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U SUBJECT TERMS Breast CancerWhere material from documents designated for limited distribution is quoted, permission has been obtained to use the material.1 Citations of commercial organizations and trade names in this report do not constitute an official Department of Army endorsement or approval of the products or services of these organizations.«PR. In conducting research using animals, the investigator(s) adhered to the "Guide for the Care and Use of Laboratory Animals," prepared by the Committee on Care and use of Laboratory Animals of the Institute of Laboratory Resources, national Research Council (NIH Publication No. 86-23, Revised 1985).For the protection of human subjects, the investigator(s) adhered to policies of applicable Federal Law 45 CFR 46. N/A In conducting research utilizing recombinant DNA technology, the investigator(s) adhered to current guidelines promulgated by the National Institutes of Health. N/A In t...

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DNA sequence analysis of hprt mutants persisting in peripheral blood of cynomolgus monkeys more than two years after ENU treatment

Cited by 3 publications

References 0 publications

The Sweet Pee Model for Sglt2 Mutation

The Sweet Pee Model for Sglt2 Mutation

An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Effect of Folate on the Efficacy and Toxicity of Cancer Chemotherapy

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