Experiment
Genetic linkage to nephritic syndrome was mapped in 160 animals from a (ICGN x MSM)F1 x ICGN backcross using 127 polymorphic markers with an average spacing of 10 cM - 20 cM. Parental strain ICGN is a mouse model for nephritic syndrome derived from inbred strain ICR. ICGN animals exhibit proteinuria, hyperlipidemia, and edema.
A locus on distal mouse Chromosome 15 at approximately 55.5 cM showed significant linkage to nephritic phenotypes at D15Mit42. Identification of 2 recombinant backcross animals localized this locus to an interval between Itga5 (57.4 cM) and D15Mit42 (55.5 cM) with a LOD score of 26.1. Twenty-two potential candidate genes mapped to this region, one of which is Tenc1. Authors previously mapped a recessive nephrosis locus, nph, to 60 cM in ICGN and MSM backcross animals. nph may be identical to the currently identified locus.
Sequence analysis revealed an 8 nucleotide deletion in exon 18of Tenc1, which is predicted to cause premature truncation of the protein product. RT-PCR analysis revealed significantly decreased Tenc1 expression in all organs of ICGN animals compared to progenitor strain ICR. In addition, Tenc1 mRNA transcript in ICGN kidneys was also significantly decreased compared to ICR kidneys. The truncated Tenc1 transcript was not observed at all. In situ hybridization using Tenc1 mRNA as a probe revealed Tenc1 expression in podocyte-like cells of the glomeruli and epithelial cellsof the tubules in normal kidneys from ICR mice, whereas Tenc1 expression in ICGN kidney sections was not detected.
Sequence analysis of Tenc1 in 8 different inbred strains was negative for the 8 base pair deletion. Therefore, the Tenc1 deletion mutation appears to be specific to the ICGN strain.
Analysis Tools