Abstract
Cystinuria is an autosomal recessive disease caused by the mutation of either SLC3A1 gene encoding for rBAT (type A cystinuria) or SLC7A9 gene encoding for b0,+AT (type B cystinuria). Here, we evidenced in a commonly used congenic 129S2/SvPasCrl mouse substrain a dramatically high frequency of kidney stones that were similar to those of patients with cystinuria. Most of 129S2/SvPasCrl exhibited pathognomonic cystine crystals in urine and an aminoaciduria profile similar to that of patients with cystinuria. In addition, we observed a heterogeneous inflammatory infiltrate and cystine tubular casts in the kidney of cystinuric mice. As compared to another classical mouse strain, C57BL/6J mice, 129S2/SvPasCrl mice had an increased mortality associated with bilateral obstructive hydronephrosis. In 129S2/SvPasCrl mice, the heavy subunit rBAT of the tetrameric transporter of dibasic amino acids was absent in proximal tubules and we identified a single pathogenic mutation in a highly conserved region of the Slc3a1 gene. This novel mouse model mimicking human disease would allow us further pathophysiological studies and may be useful to analyse the crystal/tissue interactions in cystinuria.
Highlights
Urolithiasis is one of the most frequent diseases worldwide and affects more than 10% of the population in developed countries [1,2]
We identified a typical urinary profile in five 129S2/ SvPasCrl mice displaying increased urinary excretion of cystine and dibasic aminoacids: arginine, lysine and ornithine, mimicking the aminoaciduria in humans with cystinuria (Figure 2D)
The 129 steel substrains originate from an outcross to C#HeB/ FeJ mice carrying the steel-J allele at the mast cell growth factor locus, followed by 12 to 14 generations of backcrossing to 129/Sv [12]
Summary
Urolithiasis is one of the most frequent diseases worldwide and affects more than 10% of the population in developed countries [1,2]. Cystinuria is an autosomal recessive disorder leading to cystine stone formation in kidneys and accounts for 1–2% of all cases of urolithiasis. Cystinuria holds a special position among renal stone diseases due to a high recurrence rate, associated to a frequent progression toward chronic kidney disease and renal failure [3]. The two subunits, rBAT (96 kDa) and b0,+AT (40 kDa), are linked together to form the transporter of dibasic amino acids in the brush border of the proximal tubule [5]. In vitro studies have proven that rBAT dimerizes with b0,+AT which provides the catalytic activity of the transporter. The dimer acquires a glycosylated form and its final tetrameric structure. The dimer acquires a glycosylated form and its final tetrameric structure. [6,7]
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