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  • Review Article
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The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives

Nature Reviews Nephrology volume 13, pages 115–131 (2017)Cite this article

Subjects

Key Points

  • Cystinosis is a multi-systemic lysosomal storage disease caused by inactivating mutations in, or the absence of, the lysosomal membrane exporter for cystine, cystinosin; cystinosis is the main cause of hereditary renal Fanconi syndrome

  • Treatment with cysteamine efficiently depletes lysosomal cystine and delays progression to renal insufficiency; however, cysteamine does not reverse established renal Fanconi syndrome, indicating functions of cystinosin beyond cystine transport

  • Insights from mechanistic studies suggest that the pathological mechanisms of Fanconi syndrome in cystinosis are multifactorial, involving oxidative stress and impaired vesicular trafficking, autophagy, and mTORC1 and TFEB signalling

  • Haematopoietic stem cell (HSC) transplantation ameliorates renal Fanconi syndrome in cystinotic mice; HSCs differentiate into macrophages that transfer cystinosin-bearing lysosomes into proximal tubule cells via tunnelling nanotubes that cross the tubular basement membrane

  • Since tunnelling nanotubes contain donor-derived cytosol and carry all types of organelles, this mechanism should be generic and could be used to correct other genetic diseases that affect proximal tubule cells

Abstract

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.

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Figure 1: CTNS produces two isoforms with distinct subcellular localizations.
Figure 2: Cystine crystals accumulate within lysosomes of cystinotic cells.
Figure 3: Cell biological alterations in cystinotic cells.
Figure 4: Origin and consequences of swan neck deformities.
Figure 5: Cystinosin deficiency and oxidative stress in proximal tubular cells.
Figure 6: Lysosomal membrane transport and luminal events associated with cystinosis and cysteamine therapy.
Figure 7: Proposed mechanisms by which haematopoietic stem cell (HSC) transplantation rescues cystinosis- induced Fanconi syndrome.

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Acknowledgements

S.C. and PJ.C. are funded by the Cystinosis Research Foundation, as well as NIH grants RO1-DK090058, R21-NS090066 and grant from the Sanford Stem Cell Clinical Center (to S.C.), and Belgian F.R.S./FNRS (to P.J.C.). We acknowledge Corinne Antignac, Imagine Institute, France, for her helpful comments while assembling this Review, Heloïse Gaide Chevronnay, CELL, de Duve Institute, Belgium, for her pivotal collaboration, and Patrick Van Der Smissen, CELL & PICT, de Duve Institute, Belgium, for kindly providing electron micrographs used in Fig. 2. We are also grateful to numerous colleagues who have provided so many insightful comments and contributive suggestions over the years.

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  1. Department of Pediatrics, Division of Genetics, University of California San Diego, 9500 Gilman Drive, MC 0734, La Jolla, 92093–0734, California, USA

    Stephanie Cherqui

  2. Cell biology, de Duve Institute and Université catholique de Louvain, UCL-Brussels, 75 Avenue Hippocrate, Brussels, B-1200, Belgium

    Pierre J. Courtoy

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S.C. and P.J.C. contributed equally to researching data for the article, discussion of the content, and revising or editing the manuscript before submission.

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DATABASES

MIM 219800

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Glossary

Swan neck deformities

Tubular lesions that appear in microdissected nephrons as long atrophic tubules (the 'swan necks'), appending below the glomeruli (the 'swan heads').

Founder mutations

Mutations that appear in the DNA of one or more individuals who are founders of a distinct population.

Km

Concentration of half-maximal rate. For a transporter, the Km value is inversely related to its affinity for its cargo.

Half-cystine

In biochemical assays, cystine values are reported as half-molecules because cystine was originally measured in reducing conditions (as cysteine), and cysteine is half a molecule of cystine. Cystine is now directly measured as cystine using a mass spectrometer but the values are still reported as half-cystine per mg of protein.

Lysosomal fusion

Fusion of acidified late endosomes carrying endocytic cargo with resting lysosomes bearing concentrated enzymes, or fusion between resting overloaded lysosomes (then also called interlysosomal fusion).

Lysosomal fission

Vesicular budding from endolysosomes (to regenerate late endosomes and resting lysosomes), or division of overloaded resting lysosomes into smaller ones to randomize residual content by interlysosomal fusion.

Residual body

A resting lysosome, filled with undigestible content, that no longer engages in vesicular trafficking.

Lysosomal defecation

Active exocytosis of overloaded lysosomes. This lysosomal clearing activity is stimulated by transcription factor EB.

Lysosomal amino acid sensors

Component or interacting partner of the mTOR-complex machinery that informs mTOR kinase on starvation or amino acid abundance.

Low molecular weight proteinuria

A commonly used term to describe tubular proteinuria due to defective proximal tubular endocytosis of plasma proteins selectively ultrafiltrated according to their size and/or sieving coefficient (thus excluding IgGs and other high molecular weight (MW) proteins), as opposed to non-selective glomerular leak. This terminology is convenient, but might be misleading since pure tubular proteinuria typically includes relatively high MW proteins such as transferrin (80 kDa) and even larger globular proteins.

Cross-correction

Transfer of functional protein from normal cells to deficient cells.

Pathogen spreading

Transmission of bacteria, virus or parasites from one cell to another. Bacteria and virus such as HIV have been shown to colonize cells using the tunnelling nanotube route.

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Cherqui, S., Courtoy, P. The renal Fanconi syndrome in cystinosis: pathogenic insights and therapeutic perspectives. Nat Rev Nephrol 13, 115–131 (2017). https://doi.org/10.1038/nrneph.2016.182

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