Presentation on theme: "Nephropathic cystinosis: 10th anniversary of the CTNS gene Elena Levtchenko, MD, PhD University Hospital Leuven, Belgium."— Presentation transcript:
1 Nephropathic cystinosis: 10th anniversary of the CTNS gene Elena Levtchenko, MD, PhD University Hospital Leuven, Belgium
2 Definitions Cystinosis an autosomal recessive disease caused by lysosomal accumulation of cystine due to defective exodus of cystine out of the lysosomesincidence ~1:200,000clustering in some populationsmost common cause of inherited generalized proximal tubular dysfunction(renal Fanconi syndrome)
3 Clinical forms Infantile form: Fanconi syndrome ~ 3-6 months end stage renal disease (ESRD) ~ 10 years“Late-onset” (juvenile) form:later onset (often during puberty)mild tubulopathy, more pronounced proteinuria, (even in nephrotic range)later progression to ESRDOcular formOverlap between ocular andjuvenile forms (Servais et al. 2008)3
6 Efficiency of cysteamine in cystinosis Cysteamine postpones the deterioration of the renal function(Markello et al. 1993)Cysteamine protects extra-renal organs and should be administered also after renal transplantation (Gahl et al. 2002)Topical cysteamine drops (0.5%) dissolve corneal cystine crystals (Tsilou et al. 2002). New viscous cysteamine eye preparations (Bozdag et al. 2008)BUT:Cysteamine does not reverse renal Fanconi syndromeMany patients still develop ESRD and extra-renal complications (at later age)Major compliance problems due to:- dose regimen every 6 hours (daily dose g/m2)- gastro-intestinal complaints (Dohil et al. 2006)- bad breath and sweat odor due to formation of dimethylsulfide(Besouw et al. 2007)
7 cystinosisheterozygotescontrolsCystine dysposal from granular fraction of normal, heterozygous and cystinotic cells loaded with [35S] cystine dimethyl ester
12 Expression of Cystinosin-LKG is not restricted to lysosomes Taranta et al. 2008
13 Pathogenesis of cystinosis How cystinosin defects lead to cell dysfunction in cystinosis is still unknownExisting hypotheses from in vitro studies:Cystinosin dysfunction leads to defective gluthation synthesis in cystinosis enhanced oxidative stress leading to cell damage (Levtchenko et al. 2005, Mannucci et al. 2006, Laube et al. 2006)Increased sensitivity of cystinotic cells to apoptotic stimuli due to cysteinylation of protein kinase C (Park et al. 2002, 2006) enhanced cystinotic cell deathATP deficiency cell dysfunction and Fanconi syndrome (Coor et al. 1991, Ben-Nun et al. 1993, Foreman et al. 1995, Wilmer et al. 2006)No prove in humans or in ctns -/- mice model
15 Possible functions of cystinosin-LKG Cystinosin-LKG has probably other functions in the cell additionally to lysosomal cystine transport:Cystine-binding in the cytosole: regulate cystine - cysteine pool in the cell and prevent the formation of disulfide compoundsAlternative plasma membrane cystine transporter
16 Obstacles of gene therapy in cystinosis: Molecular therapy, vol.16, No.8, , aug.2008Liver from 3-month old ctns -/- miceObstacles of gene therapy in cystinosis:Gene should be delivered to all organsUse of viral vectorsImmune responseShort duration of cystine-lowering effectGene transfer should be administered at early ageLiver from 6-month old ctns -/- mice
17 SummaryDiscovery of cystinosin in 1998 opened a new chapter of diseases caused by defects of lysosomal transport proteins.New data indicate that the expression of cystinosin is not restricted to the lysosomal membrane. Ongoing studies will identify new functions and regulators of cystinosin activity new insights into the pathogenesis of cystinosis.Gene therapy in cystinosis is feasible and is a subject of intensive research. Many obstacles should be overcome.
18 Cystinosis research group Nijmegen/Leuven Thanks toBambino Gesù Children hospital, RomeF. EmmaA. TarantaCystinosis research group Nijmegen/LeuvenVUMC, AmsterdamH. BlomM. WamelinkL.MonnensM. WilmerM. BesouwB. Van den Heuvel
20 Lysosomal membrane transport H+ADPATP?lysosomeH+H+Acid hydrolases:ProteasesGlycosidasesNucleasesPhosphatasesSulphatasesSubstrates:Amino acidsMonosaccharidesNucleosidesDi/tripeptidesInorganic ionsVitamins
21 New insights into the lysosomal membrane transport Competition experiments in isolated lysosomes predicted ~20 lysosomal transporters (Pisoni, Thoene 1991)Analogous to cystinosin: functional assays of lysosomal membrane proteins (genotype-phenotype correlations in sialic acid storage disease (Morin et al. 2004)Proteomics studies of lysosomal membrane (Schroder et al. 2007)Identification of new transporters (glucose (GLUT8), myo-inisitol (HMIT), Zn transporter, KCC1…)New genes responsible for lysosomal transport disorders (mucolipidosis type IV (MCOLN1), infantile malignant osteopetrosis (ClC7), late infantile neuronal ceroid lipofiscinosis (CLN7)
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