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Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

ABSTRACT: BACKGROUND: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age. RESULTS: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas. CONCLUSIONS: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.

SUBMITTER: Jensen JR

PROVIDER: S-EPMC4046818 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

Jensen José Ricardo JR Galvan Antonella A Borrego Andrea A Cabrera Wafa Hanna Koury WH Ribeiro Orlando Garcia OG Starobinas Nancy N De Franco Marcelo M Colecchia Maurizio M Bertolotti Alessia A Dragani Tommaso Antonio TA Ibañez Olga Célia Martinez OC

BMC genomics 20131022

<h4>Background</h4>The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, usi ...[more]

PMID: 24148528

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Project description:Diabetic animal models have made significant contributions to understanding the etiology of diabetes and to the development of new medications. Our research group recently developed a novel diabetic mouse strain, the insulin hyposecretion (ihs)mouse. The strain involves neither obesity nor insulitis but exhibits notable pancreatic β-cell dysfunction, distinguishing it from other well-characterized animal models. In ihs mice, severe impairment of insulin secretion from pancreas has been elicited by glucose or potassium chloride stimulation. To clarify the genetic basis of impaired insulin secretion, beginning with identifying the causative gene, genetic linkage analysis was performed using [(C57BL/6 × ihs) F1 × ihs] backcross progeny. Genetic linkage analysis and quantitative trait loci analysis for blood glucose after oral glucose loading indicated that a recessively acting locus responsible for impaired glucose tolerance was mapped to a 14.9-Mb region of chromosome 18 between D18Mit233 and D18Mit235 (the ihs locus). To confirm the gene responsible for the ihs locus, a congenic strain harboring the ihs locus on the C57BL/6 genetic background was developed. Phenotypic analysis of B6.ihs-(D18Mit233-D18Mit235) mice showed significant glucose tolerance impairment and markedly lower plasma insulin levels during an oral glucose tolerance test. Whole-genome sequencing and Sanger sequencing analyses on the ihs genome detected two ihs-specific variants changing amino acids within the ihs locus; both variants in Slc25a46 and Tcerg1 were predicted to disrupt the protein function. Based on information regarding gene functions involving diabetes mellitus and insulin secretion, reverse-transcription quantitative polymerase chain reaction analysis revealed that the relative abundance of Reep2 and Sil1 transcripts from ihs islets was significantly decreased whereas that of Syt4 transcripts were significantly increased compared with those of control C57BL/6 mice. Thus, Slc25a46, Tcerg1, Syt4, Reep2 and Sil1 are potential candidate genes for the ihs locus. This will be the focus of future studies in both mice and humans.

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Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

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Genetic control of renal tumorigenesis by the mouse Rtm1 locus.

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