Abstract
We report the molecular findings for the CTNS gene in 12 Turkish cystinosis patients aged 7–29 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Cystinosis was diagnosed at age 1 month to 9 years. Seven patients reached end-stage renal failure at ages ranging from 6.5 to 15 years. Whereas three of the remaining five have renal Fanconi syndrome with proteinuria, two have had kidney failure of varying degrees. Molecular analyses involved an initial multiplex polymerase chain reaction (PCR) to determine the presence or absence of the 57-kb northern European founder deletion in CTNS, followed by sequencing of the ten coding exons of CTNS. Comprehensive mutation analysis verified that none of the 12 patients carried the common 57-kb deletion. We identified four previously reported nucleotide variations associated with cystinosis and five new variants: a 10-kb deletion, three missense variants, and a nucleotide substitution in a potential branch point site of intron 4. This study is the first molecular analysis of Turkish cystinosis patients and provides guidance for the molecular diagnosis of cystinosis in this population.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N Engl J Med 347:111–121
Schneider JA, Rosenbloom FM, Bradley KH, Seegmiller JE (1967) Increased free-cystine content of fibroblasts cultured from patients with cystinosis. Biochem Biophys Res Commun 29:527–531
Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD (1982) Cystine transport is defective in isolated leukocyte lysosomes from patients with cystinosis. Science 217:1263–1265
Sonies BC, Almajid P, Kleta R, Bernardini I, Gahl WA (2005) Swallowing dysfunction in 101 patients with nephropathic cystinosis: benefit of long-term cysteamine therapy. Medicine (Baltimore) 84:137–146
Kalatzis V, Antignac C (2003) New aspects of the pathogenesis of cystinosis. Pediatr Nephrol 18:207–215
Gahl WA, Balog JZ, Kleta R (2007) Nephropathic cystinosis in adults: natural history and effects of oral cysteamine therapy. Ann Intern Med 147:242–250
Gahl WA, Reed GF, Thoene JG, Schulman JD, Rizzo WB, Jonas AJ, Denman DW, Schlesselman JJ, Corden BJ, Schneider JA (1987) Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 316:971–977
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 (1998) A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 18:319–324
Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA (1998) CTNS mutations in an American-based population of cystinosis patients. Am J Hum Genet 63:1352–1362
Kaletzis V, Nevo N, Cherqui S, Gasnier B, Antignac C (2004) Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet 13:1361–1371
Anikster Y, Shotelersuk V, Gahl WA (1999) CTNS mutations in patients with cystinosis. Hum Mutat 14:454–458
McGowan-Jordan J, Stoddard K, Podolsky L, Orrbine E, McLaine P, Town M, Goodyer P, MacKenzie A, Heick H (1999) Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. Eur J Hum Genet 7:671–678
Heil SG, Levtchenko E, Monnens LA, Trijbels FJ, Van der Put NM, Blom HJ (2001) The molecular basis of Dutch infantile nephropathic cystinosis. Nephron 89:50–55
Kalatzis V, Cherqui S, Jean G, Cordier B, Cochat P, Broyer M, Antignac C (2001) Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany. J Am Soc Nephrol 12:2170–2174
Kiehntopf M, Schickel J, Gonne B, Koch HG, Superti-Furga A, Steinmann B, Deufel T, Harms E (2002) Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis. Hum Mutat 20:237
Kleta R, Anikster Y, Lucero C, Shotelersuk V, Huizing M, Bernardini I, Park M, Thoene J, Schneider J, Gahl WA (2001) CTNS mutations in African American patients with cystinosis. Mol Genet Metab 74:332–337
Kalatzis V, Cohen-Solal L, Cordier B, Frishberg Y, Kemper M, Nuutinen EM, Legrand E, Cochat P, Antignac C (2002) Identification of 14 novel CTNS mutations and characterization of seven splice site mutations associated with cystinosis. Hum Mutat 20:439–446
Mason S, Pepe G, Dall'Amico R, Tartaglia S, Casciani S, Greco M, Bencivenga P, Murer L, Rizzoni G, Tenconi R, Clementi M (2003) Mutational spectrum of the CTNS gene in Italy. Eur J Hum Genet 11:503–508
Huizing M, Anikster Y, Fitzpatrick DL, Jeong AB, D'Souza M, Rausche M, Toro JR, Kaiser-Kupfer MI, White JG, Gahl WA (2001) Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. Am J Hum Genet 69:1022–1032
Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA (1999) Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS). Mol Genet Metab 66:111–116
Vilboux T, Kayser M, Introne W, Suwannarat P, Bernardini I, Fischer R, O'Brien K, Kleta R, Huizing M, Gahl WA (2009) Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum Mutat 30:1611–1619
Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M (1999) Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. Hum Mol Genet 8:2507–2514
Alcantara-Ortigoza MA, Belmont-Martinez L, Vela-Amieva M, Gonzalez-Del Angel A (2008) Analysis of the CTNS gene in nephropathic cystinosis Mexican patients: report of four novel mutations and identification of a false positive 57-kb deletion genotype with LDM-2/exon 4 multiplex PCR assay. Genet Test 12:409–414
Baralle D, Baralle M (2005) Splicing in action: assessing disease causing sequence changes. J Med Genet 42:737–748
Taranta A, Wilmer MJ, van den Heuvel LP, Bencivengo F, Bellomo F, Levtchenko EN, Emma F (2010) Analysis of CTNS gene transcripts in nephropathic cystinosis. Pediatr Nephrol 25:1263–1267
Aldahmesh MA, Humeidan A, Almojalli HA, Khan AO, Rajab M, AL-A AA, Meyer BF, Alkuraya FS (2009) Characterization of CTNS mutations in Arab patients with cystinosis. Ophthalmic Genet 30:185–189
Acknowledgment
We gratefully acknowledge Prof. Dr. Elena Levtchenko for her advice and help in completing the genetic analysis and the critical reading of the manuscript. Hacettepe University Nephrogenetics Laboratory was established by Hacettepe University Infrastructure Project (Project No: 06A101008)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Topaloglu, R., Vilboux, T., Coskun, T. et al. Genetic basis of cystinosis in Turkish patients: a single-center experience. Pediatr Nephrol 27, 115–121 (2012). https://doi.org/10.1007/s00467-011-1942-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-011-1942-6