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. 2005 Jan;42(1):58–68. doi: 10.1136/jmg.2004.022244

New insights into cystinuria: 40 new mutations, genotype–phenotype correlation, and digenic inheritance causing partial phenotype

M Font-Llitjos 1, M Jimenez-Vidal 1, L Bisceglia 1, P Di 1, L de Sanctis 1, F Rousaud 1, L Zelante 1, M Palacin 1, V Nunes 1
PMCID: PMC1735913  PMID: 15635077

Abstract

Objective: To clarify the genotype–phenotype correlation and elucidate the role of digenic inheritance in cystinuria.

Methods: 164 probands from the International Cystinuria Consortium were screened for mutations in SLC3A1 (type A) and SLC7A9 (type B) and classified on the basis of urine excretion of cystine and dibasic amino acids by obligate heterozygotes into 37 type I (silent heterozygotes), 46 type non-I (hyperexcretor heterozygotes), 14 mixed, and 67 untyped probands.

Results: Mutations were identified in 97% of the probands, representing 282 alleles (86.8%). Forty new mutations were identified: 24 in SLC3A1 and 16 in SLC7A9. Type A heterozygotes showed phenotype I, but mutation DupE5-E9 showed phenotype non-I in some heterozygotes. Type B heterozygotes showed phenotype non-I, with the exception of 10 type B mutations which showed phenotype I in some heterozygotes. Thus most type I probands carried type A mutations and all type non-I probands carried type B mutations. Types B and A mutations contributed to mixed type, BB being the most representative genotype. Two mixed cystinuria families transmitted mutations in both genes: double compound heterozygotes (type AB) had greater aminoaciduria than single heterozygotes in their family.

Conclusions: Digenic inheritance is an exception (two of 164 families), with a limited contribution to the aminoaciduria values (partial phenotype) in cystinuria. Further mutational analysis could focus on one of the two genes (SLC3A1 preferentially for type I and SLC7A9 for type non-I probands), while for mixed probands analysis of both genes might be required, with priority given to SLC7A9.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bauch Christian, Verrey François. Apical heterodimeric cystine and cationic amino acid transporter expressed in MDCK cells. Am J Physiol Renal Physiol. 2002 Jul;283(1):F181–F189. doi: 10.1152/ajprenal.00212.2001. [DOI] [PubMed] [Google Scholar]
  2. Bertran J., Werner A., Moore M. L., Stange G., Markovich D., Biber J., Testar X., Zorzano A., Palacin M., Murer H. Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5601–5605. doi: 10.1073/pnas.89.12.5601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bisceglia L., Calonge M. J., Dello Strologo L., Rizzoni G., de Sanctis L., Gallucci M., Beccia E., Testar X., Zorzano A., Estivill X. Molecular analysis of the cystinuria disease gene: identification of four new mutations, one large deletion, and one polymorphism. Hum Genet. 1996 Oct;98(4):447–451. doi: 10.1007/s004390050237. [DOI] [PubMed] [Google Scholar]
  4. Bisceglia L., Calonge M. J., Totaro A., Feliubadaló L., Melchionda S., García J., Testar X., Gallucci M., Ponzone A., Zelante L. Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1. Am J Hum Genet. 1997 Mar;60(3):611–616. [PMC free article] [PubMed] [Google Scholar]
  5. Bisceglia L., Purroy J., Jiménez-Vidal M., d'Adamo A. P., Rousaud F., Beccia E., Penza R., Rizzoni G., Gallucci M., Palacín M. Cystinuria type I: identification of eight new mutations in SLC3A1. Kidney Int. 2001 Apr;59(4):1250–1256. doi: 10.1046/j.1523-1755.2001.0590041250.x. [DOI] [PubMed] [Google Scholar]
  6. Botzenhart Elke, Vester Udo, Schmidt Christa, Hesse Albrecht, Halber Marc, Wagner Carsten, Lang Florian, Hoyer Peter, Zerres Klaus, Eggermann Thomas. Cystinuria in children: distribution and frequencies of mutations in the SLC3A1 and SLC7A9 genes. Kidney Int. 2002 Oct;62(4):1136–1142. doi: 10.1111/j.1523-1755.2002.kid552.x. [DOI] [PubMed] [Google Scholar]
  7. Calonge M. J., Gasparini P., Chillarón J., Chillón M., Gallucci M., Rousaud F., Zelante L., Testar X., Dallapiccola B., Di Silverio F. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet. 1994 Apr;6(4):420–425. doi: 10.1038/ng0494-420. [DOI] [PubMed] [Google Scholar]
  8. Calonge M. J., Nadal M., Calvano S., Testar X., Zelante L., Zorzano A., Estivill X., Gasparini P., Palacín M., Nunes V. Assignment of the gene responsible for cystinuria (rBAT) and of markers D2S119 and D2S177 to 2p16 by fluorescence in situ hybridization. Hum Genet. 1995 Jun;95(6):633–636. doi: 10.1007/BF00209478. [DOI] [PubMed] [Google Scholar]
  9. Cartegni Luca, Wang Jinhua, Zhu Zhengwei, Zhang Michael Q., Krainer Adrian R. ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res. 2003 Jul 1;31(13):3568–3571. doi: 10.1093/nar/gkg616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chillarón J., Estévez R., Samarzija I., Waldegger S., Testar X., Lang F., Zorzano A., Busch A., Palacín M. An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. J Biol Chem. 1997 Apr 4;272(14):9543–9549. doi: 10.1074/jbc.272.14.9543. [DOI] [PubMed] [Google Scholar]
  11. Chillarón J., Roca R., Valencia A., Zorzano A., Palacín M. Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol Renal Physiol. 2001 Dec;281(6):F995–1018. doi: 10.1152/ajprenal.2001.281.6.F995. [DOI] [PubMed] [Google Scholar]
  12. Dahlberg P. J., van den Berg, Kurtz S. B., Wilson D. M., Smith L. H. Clinical features and management of cystinuria. Mayo Clin Proc. 1977 Sep;52(9):533–542. [PubMed] [Google Scholar]
  13. Dello Strologo Luca, Pras Elon, Pontesilli Claudia, Beccia Ercole, Ricci-Barbini Vittorino, de Sanctis Luisa, Ponzone Alberto, Gallucci Michele, Bisceglia Luigi, Zelante Leopoldo. Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification. J Am Soc Nephrol. 2002 Oct;13(10):2547–2553. doi: 10.1097/01.asn.0000029586.17680.e5. [DOI] [PubMed] [Google Scholar]
  14. Feliubadaló L., Bisceglia L., Font M., Dello Strologo L., Beccia E., Arslan-Kirchner M., Steinmann B., Zelante L., Estivill X., Zorzano A. Recombinant families locate the gene for non-type I cystinuria between markers C13 and D19S587 on chromosome 19q13.1. Genomics. 1999 Sep 15;60(3):362–365. doi: 10.1006/geno.1999.5928. [DOI] [PubMed] [Google Scholar]
  15. Feliubadaló Lidia, Arbonés María Lourdes, Mañas Sandra, Chillarón Josep, Visa Joana, Rodés Margot, Rousaud Ferran, Zorzano Antonio, Palacín Manuel, Nunes Virginia. Slc7a9-deficient mice develop cystinuria non-I and cystine urolithiasis. Hum Mol Genet. 2003 Jul 15;12(17):2097–2108. doi: 10.1093/hmg/ddg228. [DOI] [PubMed] [Google Scholar]
  16. Fernández Esperanza, Carrascal Montserrat, Rousaud Ferran, Abián Joaquín, Zorzano Antonio, Palacín Manuel, Chillarón Josep. rBAT-b(0,+)AT heterodimer is the main apical reabsorption system for cystine in the kidney. Am J Physiol Renal Physiol. 2002 Sep;283(3):F540–F548. doi: 10.1152/ajprenal.00071.2002. [DOI] [PubMed] [Google Scholar]
  17. Font M. A., Feliubadaló L., Estivill X., Nunes V., Golomb E., Kreiss Y., Pras E., Bisceglia L., d'Adamo A. P., Zelante L. Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria. Hum Mol Genet. 2001 Feb 15;10(4):305–316. doi: 10.1093/hmg/10.4.305. [DOI] [PubMed] [Google Scholar]
  18. Gasparini P., Calonge M. J., Bisceglia L., Purroy J., Dianzani I., Notarangelo A., Rousaud F., Gallucci M., Testar X., Ponzone A. Molecular genetics of cystinuria: identification of four new mutations and seven polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet. 1995 Oct;57(4):781–788. [PMC free article] [PubMed] [Google Scholar]
  19. Gitomer W. L., Reed B. Y., Ruml L. A., Sakhaee K., Pak C. Y. Mutations in the genomic deoxyribonucleic acid for SLC3A1 in patients with cystinuria. J Clin Endocrinol Metab. 1998 Oct;83(10):3688–3694. doi: 10.1210/jcem.83.10.5220. [DOI] [PubMed] [Google Scholar]
  20. Goodyer P. R., Clow C., Reade T., Girardin C. Prospective analysis and classification of patients with cystinuria identified in a newborn screening program. J Pediatr. 1993 Apr;122(4):568–572. doi: 10.1016/s0022-3476(05)83537-1. [DOI] [PubMed] [Google Scholar]
  21. Goodyer P., Saadi I., Ong P., Elkas G., Rozen R. Cystinuria subtype and the risk of nephrolithiasis. Kidney Int. 1998 Jul;54(1):56–61. doi: 10.1046/j.1523-1755.1998.00957.x. [DOI] [PubMed] [Google Scholar]
  22. Harnevik L., Fjellstedt E., Molbaek A., Tiselius H. G., Denneberg T., Söderkvist P. Identification of 12 novel mutations in the SLC3A1 gene in Swedish cystinuria patients. Hum Mutat. 2001 Dec;18(6):516–525. doi: 10.1002/humu.1228. [DOI] [PubMed] [Google Scholar]
  23. Harnevik Lotta, Fjellstedt Erik, Molbaek Annette, Denneberg Torsten, Söderkvist Peter. Mutation analysis of SLC7A9 in cystinuria patients in Sweden. Genet Test. 2003 Spring;7(1):13–20. doi: 10.1089/109065703321560886. [DOI] [PubMed] [Google Scholar]
  24. Horsford J., Saadi I., Raelson J., Goodyer P. R., Rozen R. Molecular genetics of cystinuria in French Canadians: identification of four novel mutations in type I patients. Kidney Int. 1996 May;49(5):1401–1406. doi: 10.1038/ki.1996.197. [DOI] [PubMed] [Google Scholar]
  25. Leclerc Daniel, Boutros Marylise, Suh Daniel, Wu Qing, Palacin Manuel, Ellis James R., Goodyer Paul, Rozen Rima. SLC7A9 mutations in all three cystinuria subtypes. Kidney Int. 2002 Nov;62(5):1550–1559. doi: 10.1046/j.1523-1755.2002.00602.x. [DOI] [PubMed] [Google Scholar]
  26. Lee W. S., Wells R. G., Sabbag R. V., Mohandas T. K., Hediger M. A. Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. J Clin Invest. 1993 May;91(5):1959–1963. doi: 10.1172/JCI116415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Peters T., Thaete C., Wolf S., Popp A., Sedlmeier R., Grosse J., Nehls M. C., Russ A., Schlueter V. A mouse model for cystinuria type I. Hum Mol Genet. 2003 Sep 1;12(17):2109–2120. doi: 10.1093/hmg/ddg189. [DOI] [PubMed] [Google Scholar]
  28. Pineda M., Fernández E., Torrents D., Estévez R., López C., Camps M., Lloberas J., Zorzano A., Palacín M. Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem. 1999 Jul 9;274(28):19738–19744. doi: 10.1074/jbc.274.28.19738. [DOI] [PubMed] [Google Scholar]
  29. Purroy J., Bisceglia L., Jaeken J., Gasparini P., Palacín M., Nunes V. Detection of two novel large deletions in SLC3A1 by semi-quantitative fluorescent multiplex PCR. Hum Mutat. 2000;15(4):373–379. doi: 10.1002/(SICI)1098-1004(200004)15:4<373::AID-HUMU10>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  30. Reig Núria, Chillarón Josep, Bartoccioni Paola, Fernández Esperanza, Bendahan Annie, Zorzano Antonio, Kanner Baruch, Palacín Manuel, Bertran Joan. The light subunit of system b(o,+) is fully functional in the absence of the heavy subunit. EMBO J. 2002 Sep 16;21(18):4906–4914. doi: 10.1093/emboj/cdf500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Saadi I., Chen X. Z., Hediger M., Ong P., Pereira P., Goodyer P., Rozen R. Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype. Kidney Int. 1998 Jul;54(1):48–55. doi: 10.1046/j.1523-1755.1998.00956.x. [DOI] [PubMed] [Google Scholar]
  32. Schmidt C., Albers A., Tomiuk J., Eggermann K., Wagner C., Capasso G., Lahme S., Hesse A., Lang F., Zerres K. Analysis of the genes SLC7A9 and SLC3A1 in unclassified cystinurics: mutation detection rates and association between variants in SLC7A9 and the disease. Clin Nephrol. 2002 May;57(5):342–348. doi: 10.5414/cnp57342. [DOI] [PubMed] [Google Scholar]
  33. Schmidt C., Tomiuk J., Botzenhart E., Vester U., Halber M., Hesse A., Wagner C., Lahme S., Lang F., Zerres K. Genetic variations of the SLC7A9 gene: allele distribution of 13 polymorphic sites in German cystinuria patients and controls. Clin Nephrol. 2003 May;59(5):353–359. [PubMed] [Google Scholar]
  34. Schmidt Christa, Vester Udo, Wagner Carsten A., Lahme Sven, Hesse Albrecht, Hoyer Peter, Lang Florian, Zerres Klaus, Eggermann Thomas, Arbeitsgemeinschaft für Pädiatrische Nephrologie Significant contribution of genomic rearrangements in SLC3A1 and SLC7A9 to the etiology of cystinuria. Kidney Int. 2003 Nov;64(5):1564–1572. doi: 10.1046/j.1523-1755.2003.00250.x. [DOI] [PubMed] [Google Scholar]
  35. Turnell D. C., Cooper J. D. Rapid assay for amino acids in serum or urine by pre-column derivatization and reversed-phase liquid chromatography. Clin Chem. 1982 Mar;28(3):527–531. [PubMed] [Google Scholar]
  36. Wartenfeld R., Golomb E., Katz G., Bale S. J., Goldman B., Pras M., Kastner D. L., Pras E. Molecular analysis of cystinuria in Libyan Jews: exclusion of the SLC3A1 gene and mapping of a new locus on 19q. Am J Hum Genet. 1997 Mar;60(3):617–624. [PMC free article] [PubMed] [Google Scholar]

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