Abstract
Background: Nephropathic cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene, encoding for cystinosin, a carrier protein transporting cystine out of lysosomes. Its deficiency leads to cystine accumulation and cell damage in multiple organs, especially in the kidney. In this study, we aimed to provide the first report describing the mutational spectrum of Egyptian patients with nephropathic cystinosis and their genotype–phenotype correlation.
Methods: Fifteen Egyptian patients from 13 unrelated families with infantile nephropathic cystinosis were evaluated clinically, biochemically, and genetically. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the ten coding exons, exon-intron interfaces, and promoter region.
Results: None of the 15 Egyptian patients had the 57-kb deletion. Twenty-seven mutant alleles and 12 pathogenic mutations were detected including six novel mutations: two frameshift (c.260_261delTT; p.F87SfsX36, c.1032delCinsTG; p.F345CfsX19), one nonsense (c.734G>A; p.W245fsX), two missense (c.1084G>A; pG362R, c.560A>G; p.K187R), and one intronic splicing mutation (IVS3+5g>t). A novel promoter region mutation (1-593-41C>T) seemed to be detected but was excluded as a pathogenic mutation by quantitative real-time PCR analysis.
Conclusions: This study could be the basis for future genetic counseling and prenatal diagnosis of patients with nephropathic cystinosis in Egyptian and surrounding populations. The screening for the 57-kb deletion is not recommended anymore outside its geographical distribution, especially in the region of the Middle East. A common Middle Eastern mutation (c.681G>A; E227E) was pointed out and discussed.
Competing interests: None declared
Neveen A. Soliman and Mohamed A. Elmonem contributed equally to this study
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Acknowledgments
We would like to thank our patients and their parents for their kind collaboration. This work was supported by a grant from the Cystinosis Research Network (CRN) to Neveen A Soliman and Elena Levtchenko in 2012. Elena Levtchenko was supported by the Fund for Scientific Research, Flanders (F.W.O. Vlaanderen), grant 1801110 N.
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Communicated by: Verena Peters
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Synopsis
This study summarizes the Egyptian experience in the diagnosis and management of patients with nephropathic cystinosis over the past few years and reports six novel and six recurrent mutations in the CTNS gene.
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Conflict of Interest
Neveen A. Soliman, Mohamed A. Elmonem, Lambertus van den Heuvel, Rehab H. Abdel Hamid, Mohamed Gamal, Inge Bongaers, Sandrine Marie, and Elena Levtchenko declare that they have no conflict of interest regarding the contents of the current study.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consents were obtained from all patients for being included in the study.
Details of the Contributions of Individual Authors
Neveen A Soliman was involved in the conception and design of the study, recruitment and management of patients, interpretation of data, and drafting the manuscript.
Mohamed A Elmonem was involved in the conception and design of the study, biochemical and genetic analysis of patients, interpretation of data, and drafting the manuscript.
Lambertus van den Heuvel was involved in the conception and design of the study, genetic analysis of patients, interpretation of data, and revising the manuscript critically for intellectual content.
Rehab H. Abdel Hamid was involved in the design of the study, recruitment and management of patients, interpretation of data, and revising the manuscript critically for intellectual content.
Mohamed Gamal was involved in the design of the study, recruitment and management of patients, interpretation of data, and revising the manuscript critically for intellectual content.
Inge Bongaers was involved in the design of the study, genetic analysis of patients, interpretation of data, and revising the manuscript critically for intellectual content.
Sandrine Marie was involved in the design of the study, biochemical analysis of patients, interpretation of data, and revising the manuscript critically for intellectual content.
Elena Levtchenko was involved in the conception and design of the study, genetic analysis of patients, interpretation of data, and revising the manuscript critically for intellectual content.
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Soliman, N.A. et al. (2014). Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 14. JIMD Reports, vol 14. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2013_288
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DOI: https://doi.org/10.1007/8904_2013_288
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