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      Digenic Inheritance in Cystinuria Mouse Model

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          Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b 0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b 0,+AT, cause cystinuria type B. By crossing Slc3a1 -/- with Slc7a9 -/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months) and late stage (8-months) of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice ( Slc7a9 +/- Slc3a1 +/-) present lower expression of system b 0,+ and higher hyperexcretion of cystine than single heterozygotes ( Slc7a9 +/- Slc3a1 +/+ and Slc7a9 +/+ Slc3a1 +/-) and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.

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          Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (bo,+AT) of rBAT.

          Cystinuria (MIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids. Mutations in SLC3A1, encoding rBAT, cause cystinuria type I (ref. 1), but not other types of cystinuria (ref. 2). A gene whose mutation causes non-type I cystinuria has been mapped by linkage analysis to 19q12-13.1 (Refs 3,4). We have identified a new transcript, encoding a protein (bo, +AT, for bo,+ amino acid transporter) belonging to a family of light subunits of amino acid transporters, expressed in kidney, liver, small intestine and placenta, and localized its gene (SLC7A9) to the non-type I cystinuria 19q locus. Co-transfection of bo,+AT and rBAT brings the latter to the plasma membrane, and results in the uptake of L-arginine in COS cells. We have found SLC7A9 mutations in Libyan-Jews, North American, Italian and Spanish non-type I cystinuria patients. The Libyan Jewish patients are homozygous for a founder missense mutation (V170M) that abolishes b o,+AT amino-acid uptake activity when co-transfected with rBAT in COS cells. We identified four missense mutations (G105R, A182T, G195R and G295R) and two frameshift (520insT and 596delTG) mutations in other patients. Our data establish that mutations in SLC7A9 cause non-type I cystinuria, and suggest that bo,+AT is the light subunit of rBAT.
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            Comparison between SLC3A1 and SLC7A9 cystinuria patients and carriers: a need for a new classification.

            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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              Pathophysiology and treatment of cystinuria.

              Cystinuria is a primary inherited aminoaciduria caused by mutations in the genes that encode the two subunits (neutral and basic amino acid transport protein rBAT and b(0,+)-type amino acid transporter 1) of the amino acid transport system b(0,+). This autosomal recessive disorder (in which few cases show dominant inheritance) causes a failure in the reabsorption of filtered cystine and dibasic amino acids in the proximal tubule. The clinical symptoms of this disease are caused by the loss of poorly soluble cystine, which precipitates to form stones. Although rare, the prevalence of cystinuria is sufficiently high that the disease results in a substantial contribution to pediatric renal lithiasis. A thorough understanding of cystine transport processes over the past 15 years and the genetic abnormalities responsible for the disease has led to a new classification of cystinuria and recognition that some cases result from an autosomal dominant etiology with incomplete penetrance. This Review examines the molecular and mechanistic effects of some of the mutations that cause cystinuria based on our current understanding of the structural and cellular biology of system b(0,+). This Review also describes the current treatments to prevent recurrent cystine lithiasis.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                11 September 2015
                : 10
                : 9
                [1 ]Molecular Genetics Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain
                [2 ]Center for Biomedical Network Research on Rare Diseases (CIBERER), U730, Hospitalet de Llobregat, Barcelona, Spain
                [3 ]Pathology Department, Canarias University Hospital La Laguna, Tenerife, Spain
                [4 ]Center for Biomedical Network Research on Rare Diseases (CIBERER), U740, La Laguna, Tenerife, Spain
                [5 ]Institute of Research in Biomedicine (IRB), Barcelona, Spain
                [6 ]Center for Biomedical Network Research on Rare Diseases (CIBERER), U731, Barcelona, Spain
                [7 ]Biochemistry and Molecular Biology Department, Barcelona University (UB)), Barcelona, Spain
                [8 ]Genetic Section, Physiology Science II Department, Barcelona University (UB), Barcelona, Spain
                IGBMC/ICS, FRANCE
                Author notes

                Competing Interests: All authors declare that there are not conflicts of professional interest

                Conceived and designed the experiments: MP VN. Performed the experiments: ME MFLL CV ES EP. Analyzed the data: ME MFLL MLH VN. Wrote the paper: ME MP VN. Revision and discussion of the manuscript: ME MFLL CV ES EP MLH MP VN.

                ‡ These authors share equal senior authorship.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 4, Tables: 2, Pages: 12
                “Funding was provided by Instituto de Salud Carlos III, organism adscrito al Ministerio de Economía y Competitividad” and “Fondo Europeo de Desarrollo Regional (FEDER)” reference: PI13/00121 to Virginia Nunes,; Agència de Gestió d’Ajuts Universitaris i de Recerca SGR2009-1490 to Virginia Nunes and SGR2009-1355 to Manuel Palacín,; Ministerio de Economía y Competitividad SAF2012-40080 to Manuel Palacín,; SAF2011-23933 to Eduardo Salido, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
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