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  • Review Article
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Pathophysiology and treatment of cystinuria

Nature Reviews Nephrology volume 6, pages 424–434 (2010)Cite this article

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Abstract

Cystinuria is a primary inherited aminoaciduria caused by mutations in the genes that encode the two subunits (neutral and basic amino acid transport protein rBAT and b(0,+)-type amino acid transporter 1) of the amino acid transport system b0,+. This autosomal recessive disorder (in which few cases show dominant inheritance) causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule. The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones. Although rare, the prevalence of cystinuria is sufficiently high that the disease results in a substantial contribution to pediatric renal lithiasis. A thorough understanding of cystine transport processes over the past 15 years and the genetic abnormalities responsible for the disease has led to a new classification of cystinuria and recognition that some cases result from an autosomal dominant etiology with incomplete penetrance. This Review examines the molecular and mechanistic effects of some of the mutations that cause cystinuria based on our current understanding of the structural and cellular biology of system b0,+. This Review also describes the current treatments to prevent recurrent cystine lithiasis.

Key Points

  • Cystinuria is characterized by the inadequate reabsorption of cystine and dibasic amino acids in the kidney, which leads to the hyperexcretion of these amino acids in urine

  • Cystinuria represents 1–2% of all cases of renal lithiasis and 6–8% of cases of pediatric renal lithiasis

  • The amino acid transport system b0,+ is the main effector of cystine reabsorption in the kidney

  • The functional unit of the system b0,+ comprises a heterodimer in which the neutral and basic amino acid transport protein rBAT (rBAT) is linked via a disulfide bridge to b(0,+)-type amino acid transporter 1 (b0,+AT)

  • Mutations in either rBAT or b0,+AT can cause cystinuria; mutations in the gene that encodes rBAT cause trafficking defects probably due to protein misfolding and mutations in the gene that encodes b0,+AT cause trafficking defects or inactivation of system b0,+

  • Two genetically modified mouse lines exhibit the features of the two main types of cystinuria, type I cystinuria and non-type I cystinuria

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Figure 1: Trafficking of cystine and dibasic amino acids in epithelial cells of the renal proximal tubule or small intestine.
Figure 2: 3D model of the amino acid transport system b0,+.
Figure 3
Figure 4: The '5+5' inverted repeat fold of APC transporters.

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Acknowledgements

Dr. Chillarón receives support from the Spanish Ministry of Science and Innovation, grant BFU2009-07-215. Dr. Goldfarb receives support from the National Institutes of Diabetes and Digestive and Kidney Diseases and the Office of Rare Diseases Research, grant 1U54DK083908-01. Dr. Nunes and Dr. Palacín receive support from the Spanish Ministry of Science and Innovation, grants BFU2006-14, 600-C02-01 and BFU2006-14-600-C02-02, and SAF2009-12606-C02-01 and SAF2009-12606-C02-02, from the Center for Biomedical Research on Rare Diseases (CIBERER), from the European Commission, grant EDICT and from Generalitat de Catalunya 2009 SGR 1355 and 2009 SGR 1490.

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Authors and Affiliations

  1. Department of Physiology, Faculty of Biology, Universitat de Barcelona, Diagonal 645, 08028, Barcelona, Spain

    Josep Chillarón

  2. Molecular Genetics Department, IDIBELL-CIBERER U730, Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08907, Barcelona, Spain

    Mariona Font-Llitjós

  3. Institute for Research in Biomedicine and CIBERER U731, Baldiri I Reixac 10, 08028, Barcelona, Spain

    Joana Fort & Manuel Palacín

  4. Institute for Research in Biomedicine, Baldiri I Reixac 10, 08028, Barcelona, Spain

    Antonio Zorzano

  5. Nephrology Section/111G, New York Harbor VA Medical Center, New York, 10010, NY, USA

    David S. Goldfarb

  6. Department of Physiological Sciences, Genetic Unit, Universitat de Barcelona-IDIBELL, Feixa Llarga s/n, L'Hospitalet de Llobregat, 08907, Barcelona, Spain

    Virginia Nunes

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  1. Josep Chillarón
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  2. Mariona Font-Llitjós
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  3. Joana Fort
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  7. Manuel Palacín
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Corresponding author

Correspondence to Manuel Palacín.

Supplementary information

Supplementary Figure 1

Alignment of human b0,+AT and Escherichia coli AdiC. (DOC 37 kb)

Supplementary Figure 2

Structural alignment of human rBAT ectodomain (ED-rBAT) and GH13 α-glucosidase. (DOC 43 kb)

Supplementary Table 1

Frequency of the reported SLC3A1 mutations associated with cystinuria. (DOC 974 kb)

Supplementary Table 2

Frequency of the SLC7A9 mutations reported. (DOC 560 kb)

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Chillarón, J., Font-Llitjós, M., Fort, J. et al. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol 6, 424–434 (2010). https://doi.org/10.1038/nrneph.2010.69

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