Human Molecular Genetics Advance Access published online on May 5, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh152
© 2004 by Oxford University Press
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1 Inserm U574, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France; Present address: Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, France
* To whom correspondence should be addressed. E-mail: kalatzis{at}igm.cnrs-mop.fr.
Cystinosis is an inherited disorder characterised by defective lysosomal efflux of cystine. Three clinical forms (infantile, juvenile and ocular cystinosis) have been described according to age of onset and severity of the symptoms. The causative gene, CTNS, encodes a 7 transmembrane domain (TM) protein, cystinosin, which we recently identified as a H+-driven cystine transporter using an in vitro transport assay. In this study, we explored the relationship between transport activity and intracellular localisation of cystinosin mutants and their associated clinical phenotype. Thirty-one pathogenic mutations (24 missense mutations, 7 in-frame deletions or insertions) were analysed. Most mutations did not alter the lysosomal localisation of cystinosin, although 3 partially mislocalised the protein independently of its C-terminal sorting motif, thus confirming the presence of an additional sorting mechanism. Sixteen of 19 mutations associated with infantile cystinosis abolished transport whereas 3 of 5 mutations associated with juvenile or ocular forms strongly reduced transport, in agreement with the milder clinical phenotype. Five atypical, unclassified or misclassified mutations could be clarified using the transport data and additional genetic information. Overall, our data demonstrates that, excluding premature termination of cystinosin, impaired transport is the most frequent cause of pathogenicity, with infantile cystinosis generally resulting from a total loss of activity. The transport assay could thus be used as a prognostic tool when novel mutations are identified.
Article
Molecular pathogenesis of cystinosis: Effect of CTNS mutations on the transport activity and subcellular localisation of cystinosin
2 Inserm U574, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
3 CNRS UPR 1929, Institut de Biologie Physico-Chimique, 13 rue Pierre et Marie Curie, 75005 Paris, France
4 Inserm U574, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France; Department of Genetics, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France
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