Cystinuria: genetic aspects, mouse models, and a new approach to therapy

Abstract

Cystinuria, a genetic disorder of cystine transport, is characterized by excessive excretion of cystine in the urine and recurrent cystine stones in the kidneys and, to a lesser extent, in the bladder. Males generally are more severely affected than females. The disorder may lead to chronic kidney disease in many patients. The cystine transporter (b 0,+ ) is a heterodimer consisting of the rBAT (encoded by SLC3A1) and b 0,+ AT (encoded by SLC7A9) subunits joined by a disulfide bridge. The molecular basis of cystinuria is known in great detail, and this information is now being used to define genotype-phenotype correlations. Current treatments for cystinuria include increased fluid intake to increase cystine solubility and the administration of thiol drugs for the more severe cases. These drugs, however, have poor patient compliance due to adverse effects. Thus, there is a need to reduce or eliminate the risks associated with therapy for cystinuria. Four mouse models for cystinuria have been described and these models provide a resource for evaluating the safety and efficacy of new therapies for cystinuria. We are evaluating a new approach for the treatment of cystine stones based on the inhibition of cystine crystal growth by cystine analogs. Our ongoing studies indicate that cystine diamides are effective in preventing cystine stone formation in the Slc3a1 knockout mouse model for cystinuria. In addition to crystal growth, crystal aggregation is required for stone formation. Male and female mice with cystinuria have comparable levels of crystalluria, but very few female mice form stones. The identification of

Empirical therapy or precision medicine for kidney stone formers in the ‘-omics’ era?

“…For many disorders, our more in-depth knowledge has yet to generate targeted therapies, but the two articles on the primary hyperoxalurias [13,14] paint an encouraging picture for the diagnosis and treatment of these very rare, severe disorders. The same applies to the issue of cystinuria, which holds a promise brilliantly illustrated by Sahota et al [15].…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…Manifesting heterozygous individuals suggest that cystinuria type B can be transmitted in an autosomal dominant inheritance pattern with incomplete penetrance [84]. Global prevalence and disease severity appear to be the same in cystinuria types A and B [66]. It is possible that there is a very rare third type of cystinuria caused by a mutation in each of the two previously mentioned genes (cystinuria type AB), but it still needs to be confirmed in order to demonstrate the digenic inheritance of cystinuria [80].…”

“…Cystinuria is a common genetic disorder caused by defective transport of cystine and dibasic amino acids (ornithine, lysine, and arginine) across the apical membrane of epithelial cells in the renal proximal tubules and the gastrointestinal tract mediated by the b 0,+ transporter [21,[56][57][58][59][60][61][62][63][64][65][66]. The b 0,+ transporter is a heterodimer comprising rBAT (encoded by SLC3A1) and b 0,+ AT (encoded by SLC7A9) subunits linked by a disulfide bridge [67][68][69][70].…”

“…In general, men are affected more severely than women and have a higher number of stones [61]. A diagnosis is usually established by confirming that stones are composed of cystine [66]. Cystine stone formation may lead to complications such as obstructive uropathy and pyelonephritis.…”

Genetic and Clinical Analyses of 13 Chinese Families With Cystine Urolithiasis and Identification of 15 Novel Pathogenic Variants in SLC3A1 and SLC7A9

“…b0,+ and b0,+AT combine with each other through disulfide linkage, and only the combined b0,+-b0,+AT heterodimer is functional (Chillarón et al, 2010). The inheritance for cystinuria may vary from autosomal recessive (AR) to autosomal dominant (AD) with incomplete penetrance to digenic pattern (Dello Strologo et al, 2002;Sahota et al, 2019). Accordingly, cystinuria is divided into the following subtypes: biallelic SLC3A1 mutations (AA genotype), biallelic SLC7A9 mutations (BB genotype), a single heterozygous SLC3A1 mutation (A genotype), a single heterozygous SLC7A9 mutation (B genotype), and a single heterozygous SLC3A1 mutation combined with a single heterozygous SLC7A9 mutation (AB genotype) (Dello Strologo et al, 2002;Sahota et al, 2019).…”