The Molecular Basis of Cystinuria

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Abstract

Cystinuria is an inherited form of nephrolithiasis due to failure of reabsorptive transport in the proximal tubule. Patients with classical recessive cystinuria have inherited two mutations of the SLC3A1 gene, encoding a subunit of the transport mechanism. Patients with the dominant form of cystinuria have inherited two mutations of the SLC7A9 gene, encoding the transport channel itself. A smaller subset of patients have mixed-type cystinuria, combining recessive and dominant mutant alleles. Children at risk for nephrolithiasis can be identified by the level of urinary cystine only after tubular transport has matured (age 2 years). Conservative therapy with high urine volume and urinary alkalinization is sufficient for some, but recurrent stone formation may cause renal damage and warrants prophylaxis with agents that form mixed disulfides with cystine.

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Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine.

Teresa Calonge, F Di Corte, P Gasparini … (1994)

Cystinuria is a classic heritable aminoaciduria that involves the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine. Six missense mutations in the human rBAT gene, which is involved in high-affinity transport of cystine and dibasic amino acids in kidney and intestine, segregate with cystinuria. These mutations account for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation (M467T) was detected in three cystinuric siblings. Mutation M467T nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. These results establish rBAT as a cystinuria gene.

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Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

Mariona Font-Llitjós, Claudia Pontesilli, Luigi Bisceglia … (2002)

Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients.

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Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

M. Angels Font, P Gasparini, P. D'Adamo … (2001)

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine. Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria. Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients. These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found. Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids. Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity. In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved amino acid residues with a small side chain generate a severe phenotype, while mutations in non-conserved residues give rise to a mild phenotype. These data provide the first genotype-phenotype correlation in non-Type I cystinuria, and show that a mild urinary phenotype in heterozygotes may associate with mutations with significant residual transport activity.

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Author and article information

Journal

Journal ID (publisher-id): NEE

Journal ID (nlm-ta): Nephron Exp Nephrol

Journal ID (doi): 10.1159/issn.1660-2129

Title: Cardiorenal Medicine

Publisher: S. Karger AG

ISBN: 978-3-8055-7852-3

ISBN: 978-3-318-06156-7

ISSN (Electronic): 1660-2129

Publication date Subscription-year: 2004

Publication date (Print): October 2004

Publication date (Electronic): 17 November 2004

Volume: 98

Issue: 2

Pages: e45-e49

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Department of Pediatrics, McGill University, Montreal Children’s Hospital, Montreal, Canada

Article

Publisher ID: 80255 Other ID: Nephron Exp Nephrol 2004;98:e45–e49

DOI: 10.1159/000080255

PubMed ID: 15499206

SO-VID: 3cf075c2-ec20-45be-875d-0d5306c30e76

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The Molecular Basis of Cystinuria

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Karger: Nephrology

Most cited references 28

Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine.

Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria.

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