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

M. Font-Llitjós, M. Jiménez-Vidal, L. Bisceglia, M. Di Perna, L. De Sanctis, F. Rousaud, L. Zelante, M. Palacín, Virginia Nunes

Research output: Contribution to journalArticle

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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% or 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.

Original languageEnglish
Pages (from-to)58-68
Number of pages11
JournalJournal of Medical Genetics
Volume42
Issue number1
DOIs
Publication statusPublished - Jan 2005

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Cystinuria
Genetic Association Studies
Heterozygote
Phenotype
Mutation
Diamino Amino Acids
Genes
Cystine
Alleles
Genotype
Urine

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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New insights into cystinuria : 40 New mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. / Font-Llitjós, M.; Jiménez-Vidal, M.; Bisceglia, L.; Di Perna, M.; De Sanctis, L.; Rousaud, F.; Zelante, L.; Palacín, M.; Nunes, Virginia.

In: Journal of Medical Genetics, Vol. 42, No. 1, 01.2005, p. 58-68.

Research output: Contribution to journalArticle

Font-Llitjós, M, Jiménez-Vidal, M, Bisceglia, L, Di Perna, M, De Sanctis, L, Rousaud, F, Zelante, L, Palacín, M & Nunes, V 2005, 'New insights into cystinuria: 40 New mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype', Journal of Medical Genetics, vol. 42, no. 1, pp. 58-68. https://doi.org/10.1136/jmg.2004.022244
Font-Llitjós, M. ; Jiménez-Vidal, M. ; Bisceglia, L. ; Di Perna, M. ; De Sanctis, L. ; Rousaud, F. ; Zelante, L. ; Palacín, M. ; Nunes, Virginia. / New insights into cystinuria : 40 New mutations, genotype-phenotype correlation, and digenic inheritance causing partial phenotype. In: Journal of Medical Genetics. 2005 ; Vol. 42, No. 1. pp. 58-68.
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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{\%} or 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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AU - Font-Llitjós, M.

AU - Jiménez-Vidal, M.

AU - Bisceglia, L.

AU - Di Perna, M.

AU - De Sanctis, L.

AU - Rousaud, F.

AU - Zelante, L.

AU - Palacín, M.

AU - Nunes, Virginia

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N2 - 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% or 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.

AB - 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% or 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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