Journal Mobile Options
Table of Contents
Vol. 89, No. 1, 2001
Issue release date: 2001

The Molecular Basis of Dutch Infantile Nephropathic Cystinosis

Heil S.G. · Levtchenko E. · Monnens L.A.H. · Trijbels F.J.M. · van der Put N.M.J. · Blom H.J.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

Infantile nephropathic cystinosis, an inborn error of metabolism with an autosomal recessive inheritance pattern, is characterized by lysosomal storage of the amino acid cystine due to an impaired transport of cystine out of the lysosomes. Initial clinical features consist of the renal Fanconi syndrome and crystals in the cornea. Oral therapy with cysteamine lowers the intracellular cystine content. Recently, the gene coding for the integral membrane protein cystinosin, which is responsible for membrane transport of cystine (CTNS), was cloned. Mutation analysis of the CTNS gene of Caucasian patients revealed a common 57-kb deletion, and several other mutations spread throughout the entire gene. In the present study, we developed an improved screening method for the detection of the common 57-kb deletion. By use of this method we detected the 57-kb deletion in 59% of the examined Dutch alleles. The remaining alleles were screened for other mutations by genomic sequencing of the different exons, revealing three previously described mutations. Furthermore, we studied a possible genotype-phenotype relation of the homozygous deleted patients, which could not be demonstrated in our study population. Next to biochemical determination of cystine in leukocytes or fibroblasts, molecular genetic analysis enables prenatal diagnosis and facilitates identification of carriers.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Gahl WA: Cystinosis coming of age. Adv Pediatr 1986;33:95–126.

    External Resources

  2. Chan AM, Lynch MJ, Bailey JD, Ezrin C, Fraser D: Hypothyroidism in cystinosis. A clinical, endocrinologic and histologic study involving sixteen patients with cystinosis. Am J Med 1970;48:678–692.

    External Resources

  3. Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ, Denman DW, Schlesselman JJ, Corden BJ, Schneider JA: Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 1987;316:971–977.

    External Resources

  4. Gahl WA, Tietze F, Butler JD, Schulman JD: Cysteamine depletes cystinotic leucocyte granular fractions of cystine by the mechanism of disulphide interchange. Biochem J 1985;228:545–550.

    External Resources

  5. de Graaf-Hess A, Trijbels F, Blom H: New method for determining cystine in leukocytes and fibroblasts. Clin Chem 1999;45:2224–2228.
  6. Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van’t Hoff W, Antignac C: A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis: Nat Genet 1998;18:319–324.
  7. Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA: CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet 1998;63:1352–1362.
  8. Attard M, Jean G, Forestier L, Cherqui S, van’t Hoff W, Broyer M, Antignac C, Town M: Severity of phenotype in cystinosis varies with mutations in the CTNS gene: Predicted effect on the model of cystinosin. Hum Mol Genet 1999;8:2507–2514.

    External Resources

  9. Forestier L, Jean G, Attard M, Cherqui S, Lewis C, van’t Hoff W, Broyer M, Town M, Antignac C: Molecular characterization of CTNS deletions in nephropathic cystinosis: Development of a PCR-based detection assay. Am J Hum Genet 1999;65:353–359.
  10. Thoene J, Lemons R, Anikster Y, Mullet J, Paelicke K, Lucero C, Gahl W, Schneider J, Shu SG, Campbell HT: Mutations of CTNS causing intermediate cystinosis. Mol Genet Metab 1999;67:283–293.
  11. Miller SA, Dykes DD, Polesky HF: A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988;16:1215.
  12. Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA: Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene. Mol Genet Metab 1999;66:111–116.
  13. Anikster Y, Shotelersuk V, Gahl WA: CTNS mutations in patients with cystinosis. Hum Mutat 1999;14:454–458.
  14. Anikster Y, Lucero C, Guo J, Huizing M, Shotelersuk V, Bernardini I, McDowell G, Iwata F, Kaiser-Kupfer MI, Jaffe R, Thoene J, Schneider JA, Gahl WA: Ocular nonnephropathic cystinosis: Clinical, biochemical, and molecular correlations. Pediatr Res 2000;47:17–23.
  15. Hunziker W, Geuze HJ: Intracellular trafficking of lysosomal membrane proteins. Bioessays 1996;18:379–389.
  16. Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED: The genomic region encompassing the nephropathic cystinosis gene: Complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion. Genome Res 2000;10:165–173.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50