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Luigi Bisceglia - One of the best experts on this subject based on the ideXlab platform.
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Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients.
Molecular genetics and metabolism, 2010Co-Authors: Luigi Bisceglia, Lucia Fischetti, Patrizia De Bonis, Orazio Palumbo, Bartolomeo Augello, Pietro Stanziale, Massimo Carella, Leopoldo ZelanteAbstract:Abstract Cystinuria is a rare inherited disorder characterized by defective renal reabsorption of cystine and the dibasic amino acids. SLC3A1 and SLC7A9 have been identified as responsible genes. The large majority of the more than 200 mutations so far identified in the two genes are point mutations, while only few alleles carrying gross genomic alterations have been reported. We screened 39 cystinuric patients for large rearrangements, by two home-made multiplex ligation-dependent probe amplification (MLPA) assays. MLPA analysis led to the identification of 6 different alleles in SLC3A1 and 2 in SLC7A9 accounting for a total of 25 copy number changes, 11 in SLC3A1 and 14 in SLC7A9 . Three large rearrangements in SLC3A1 , deletion of exons 2–4 (E2_E4del), deletion of exons 5–6 (E5_E6del) and duplication of exons 8–9 (E8_E9dup) are novel. A complete SLC7A9 gene deletion was found in three patients. In addition, we report the identification of three novel point mutations in SLC7A9 (p.G105E, p.R250K, c.1416_1417insAC), the frequency and the occurrence of cystinuria mutations in a cohort of 172 Italian patients. In conclusion, we developed a reliable and robust MLPA analytic method for SLC3A1 and SLC7A9 genes that represents an optimal complement to DNA sequence analysis in patients with cystinuria, enabling the screening for deletions and duplications.
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Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes.
Genetic testing, 2008Co-Authors: Michele Di Perna, Elon Pras, Lucia Fischetti, Pietro Stanziale, Leopoldo Zelante, Eirini Louizou, George Dedoussis, Helen Michelakakis, Luigi BiscegliaAbstract:Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria (OMIM 220100), an autosomal recessive disorder of amino acid transport and reabsorption in the proximal renal tubule and in the epithelial ...
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New insights into cystinuria: 40 new mutations, genotype–phenotype correlation, and digenic inheritance causing partial phenotype
Journal of medical genetics, 2005Co-Authors: Mariona Font-llitjós, Manuel Palacín, Luigi Bisceglia, Leopoldo Zelante, Ferran Rousaud, L. De Sanctis, Maite Jiménez-vidal, M. Di Perna, Virginia NunesAbstract: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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Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification
Journal of the American Society of Nephrology : JASN, 2002Co-Authors: Luca Dello Strologo, Elon Pras, Luigi Bisceglia, Ercole Beccia, Michele Gallucci, Alberto Ponzone, C. Pontesilli, Vittorino Ricci-barbini, Luisa De Sanctis, Leopoldo ZelanteAbstract: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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Detection of two novel large deletions in SLC3A1 by semi-quantitative fluorescent multiplex PCR.
Human mutation, 2000Co-Authors: Jesús Purroy, Manuel Palacín, Jaak Jaeken, Luigi Bisceglia, Paolo Gasparini, Virginia NunesAbstract:Cystinuria is an autosomal recessive aminoaciduria in which two clinical types have been described (type I and non-type I). Cystinuria type I is caused by mutations in SLC3A1, a gene located in 2p16 coding for an amino acid transporter named rBAT. Using multiplex semi-quantitative fluorescent PCR, we amplified the ten exons of SLC3A1 together with exon 5 of DSCR1 (located on chromosome 21) as a double-dose control gene. We detected two large novel deletions in a Belgian family, one comprising exons 2–10 and another one at exon 10. The method described here can be used to detect a range of deletions from single-base differences in size to entire missing exons, making it useful for scanning genes with a small to medium number of exons. Hum Mutat 15:373–379, 2000. © 2000 Wiley-Liss, Inc.
Leopoldo Zelante - One of the best experts on this subject based on the ideXlab platform.
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Large rearrangements detected by MLPA, point mutations, and survey of the frequency of mutations within the SLC3A1 and SLC7A9 genes in a cohort of 172 cystinuric Italian patients.
Molecular genetics and metabolism, 2010Co-Authors: Luigi Bisceglia, Lucia Fischetti, Patrizia De Bonis, Orazio Palumbo, Bartolomeo Augello, Pietro Stanziale, Massimo Carella, Leopoldo ZelanteAbstract:Abstract Cystinuria is a rare inherited disorder characterized by defective renal reabsorption of cystine and the dibasic amino acids. SLC3A1 and SLC7A9 have been identified as responsible genes. The large majority of the more than 200 mutations so far identified in the two genes are point mutations, while only few alleles carrying gross genomic alterations have been reported. We screened 39 cystinuric patients for large rearrangements, by two home-made multiplex ligation-dependent probe amplification (MLPA) assays. MLPA analysis led to the identification of 6 different alleles in SLC3A1 and 2 in SLC7A9 accounting for a total of 25 copy number changes, 11 in SLC3A1 and 14 in SLC7A9 . Three large rearrangements in SLC3A1 , deletion of exons 2–4 (E2_E4del), deletion of exons 5–6 (E5_E6del) and duplication of exons 8–9 (E8_E9dup) are novel. A complete SLC7A9 gene deletion was found in three patients. In addition, we report the identification of three novel point mutations in SLC7A9 (p.G105E, p.R250K, c.1416_1417insAC), the frequency and the occurrence of cystinuria mutations in a cohort of 172 Italian patients. In conclusion, we developed a reliable and robust MLPA analytic method for SLC3A1 and SLC7A9 genes that represents an optimal complement to DNA sequence analysis in patients with cystinuria, enabling the screening for deletions and duplications.
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Twenty-four novel mutations identified in a cohort of 85 patients by direct sequencing of the SLC3A1 and SLC7A9 cystinuria genes.
Genetic testing, 2008Co-Authors: Michele Di Perna, Elon Pras, Lucia Fischetti, Pietro Stanziale, Leopoldo Zelante, Eirini Louizou, George Dedoussis, Helen Michelakakis, Luigi BiscegliaAbstract:Mutations in the SLC3A1 and SLC7A9 genes cause cystinuria (OMIM 220100), an autosomal recessive disorder of amino acid transport and reabsorption in the proximal renal tubule and in the epithelial ...
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New insights into cystinuria: 40 new mutations, genotype–phenotype correlation, and digenic inheritance causing partial phenotype
Journal of medical genetics, 2005Co-Authors: Mariona Font-llitjós, Manuel Palacín, Luigi Bisceglia, Leopoldo Zelante, Ferran Rousaud, L. De Sanctis, Maite Jiménez-vidal, M. Di Perna, Virginia NunesAbstract: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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Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification
Journal of the American Society of Nephrology : JASN, 2002Co-Authors: Luca Dello Strologo, Elon Pras, Luigi Bisceglia, Ercole Beccia, Michele Gallucci, Alberto Ponzone, C. Pontesilli, Vittorino Ricci-barbini, Luisa De Sanctis, Leopoldo ZelanteAbstract: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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Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Maria Julia Calonge, Antonio Zorzano, Luigi Bisceglia, Leopoldo Zelante, V. Volpini, Ferran Rousaud, L. De Sanctis, Ercole Beccia, Xavier Testar, Xavier EstivillAbstract:Abstract Cystinuria is an autosomal recessive amino-aciduria where three urinary phenotypes have been described (I, II, and III). An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. To assess whether mutations in SLC3A1 are involved in different cystinuria phenotypes, linkage with this gene and its nearest marker (D2S119) was analyzed in 22 families with type I and/or type III cystinuria. Linkage with heterogeneity was proved (alpha = 0.45; P 3.0 at theta = 0.00; alpha = 1), whereas types I/III and III/III were not linked. Our data suggest that type I cystinuria is due to mutations in the SLC3A1 gene, whereas another locus is responsible for type III. This result establishes genetic heterogeneity for cystinuria, classically considered as a multiallelic monogenic disease.
John W.m. Creemers - One of the best experts on this subject based on the ideXlab platform.
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Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia–cystinuria syndrome
BMJ case reports, 2009Co-Authors: B Chabrol, Katrin Martens, Sandra Meulemans, Aline Cano, Jaak Jaeken, Gert Matthijs, John W.m. CreemersAbstract:Hypotonia–cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency. We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome.
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deletion of c2orf34 prepl and SLC3A1 causes atypical hypotonia cystinuria syndrome
Case Reports, 2009Co-Authors: B Chabrol, Sandra Meulemans, Aline Cano, Jaak Jaeken, Gert Matthijs, Kevin Martens, John W.m. CreemersAbstract:Hypotonia–cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency. We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome.
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Multi-system disorder syndromes associated with cystinuria type I.
Current molecular medicine, 2008Co-Authors: Katrin Martens, Jaak Jaeken, Gert Matthijs, John W.m. CreemersAbstract:Cystinuria type I is an autosomal recessive disorder with an exclusively renal phenotype caused by inactivating mutations in SLC3A1. Recently 3 similar but distinct syndromes associated with cystinuria type I have been described: 2p21 deletion syndrome, Hypotonia-Cystinuria Syndrome (HCS) and atypical HCS. Genetic analysis indicated that these are recessive contiguous gene deletion syndromes which differ in the number of genes affected. Patients with HCS are missing both alleles of SLC3A1 and PREPL. In atypical HCS an additional gene (C2orf34) is deleted, and finally, in the 2p21 deletion syndrome the open reading frame of PPM1B is also disrupted. With the exception of SLC3A1, the gene products have not been fully characterized. The severity of the different syndromes reflects the number of genes which are deleted. HCS, a relatively mild syndrome, is characterised by cystinuria type I, generalised hypotonia at birth, growth retardation and minor facial dysmorphic features. On the other end of the spectrum is the 2p21 deletion syndrome, a severe syndrome with a number of additional features including a moderate to severe psychomotor retardation and a decrease in activity of the respiratory chain complexes I, III, IV and V. Finally, atypical HCS displays an intermediate phenotype comparable with classical HCS but associated with mild to moderate mental retardation and a decrease in activity of only the respiratory chain complex IV. “This review will focus on the phenotypic similarities and differences observed in these syndromes. Furthermore,we speculate on the function of the gene products, based on the available data.”
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Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia–cystinuria syndrome
Journal of medical genetics, 2008Co-Authors: B Chabrol, Katrin Martens, Sandra Meulemans, Aline Cano, Jaak Jaeken, Gert Matthijs, John W.m. CreemersAbstract:Background: Hypotonia-Cystinuria syndrome (HCS) and 2p21 deletion syndrome are 2 recessive contiguous gene deletion syndromes associated with cystinuria type I. The deletions differ in size and the number of genes involved. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome 2 additional genes (C2orf34 and PPM1B) are lost. Objective: Clinical and molecular analysis of 2 siblings who presented with an atypical HCS phenotype. Methods: Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using qPCR methods. Results: HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including 3 genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency documented in patient 2. Conclusions: We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome. These patients facilitate the elucidation of the contribution of each gene to the phenotype in the different 2p21 deletion syndromes.
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deletion of c2orf34 prepl and SLC3A1 causes atypical hypotonia cystinuria syndrome
Journal of Medical Genetics, 2008Co-Authors: B Chabrol, Sandra Meulemans, Aline Cano, Jaak Jaeken, Gert Matthijs, Kevin Martens, John W.m. CreemersAbstract:Background: Hypotonia-Cystinuria syndrome (HCS) and 2p21 deletion syndrome are 2 recessive contiguous gene deletion syndromes associated with cystinuria type I. The deletions differ in size and the number of genes involved. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome 2 additional genes (C2orf34 and PPM1B) are lost. Objective: Clinical and molecular analysis of 2 siblings who presented with an atypical HCS phenotype. Methods: Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using qPCR methods. Results: HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including 3 genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency documented in patient 2. Conclusions: We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome. These patients facilitate the elucidation of the contribution of each gene to the phenotype in the different 2p21 deletion syndromes.
Thomas Eggermann - One of the best experts on this subject based on the ideXlab platform.
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No evidence for point mutations in the novel renal cystine transporter AGT1/SLC7A13 contributing to the etiology of cystinuria
BMC nephrology, 2018Co-Authors: Kathrin Olschok, Udo Vester, Sven Lahme, Ingo Kurth, Thomas EggermannAbstract:Cystinuria is caused by the defective renal reabsorption of cystine and dibasic amino acids, and results in cystine stone formation. So far, mutations in two genes have been identified as causative. The SLC3A1/rBAT gene encodes the heavy subunit of the heterodimeric rBAT-b0,+AT transporter, whereas the light chain is encoded by the SLC7A9/ b0,+AT gene. In nearly 85% of patients mutations in both genes are detectable, but a significant number of patients currently remains without a molecular diagnosis. Thus, the existence of a further cystinuria gene had been suggested, and the recently identified AGT1/SLC7A13 represents the long-postulated partner of rBAT and third cystinuria candidate gene. We screened a cohort of 17 cystinuria patients for SLC7A13 variants which were negative for SLC3A1 and SLC7A9 mutations. Despite strong evidences for an involvement of SLC7A13 mutations in cystinuria, we could not confirm a relevant role of SLC7A13 for the disease. With the exclusion of SLC7A13/AGT1 as the third cystinuria gene accounting for the SLC3A1 and SLC7A9 mutation negative cases, it becomes obvious that other genetic factors should be responsible for the cystinuria phenotype in nearly 15% of patients.
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eLS - Molecular Genetics of Cystinuria
eLS, 2012Co-Authors: Thomas EggermannAbstract:Among the kidney stone diseases, cystinuria (OMIM 220100) is unique as it is exclusively caused by genomic alterations. Cystinuria is associated with mutations in the SLC3A1 and the SLC7A9 genes encoding the subunits rBAT and b0,+AT of the renal b0,+ transporter. Mutations in SLC3A1 are usually inherited autosomal recessively, but SLC7A9 mutations result in a broad clinical variability. The detection rate for mutations is influenced by the ethnic origin of the patient and by the functional significance of the variant. As a result, mutations cannot be detected in 100% of alleles, but it reaches approximately 85%. In case of SLC3A1, large rearrangements in 2p21 cause cystinuria and severe hypotonia (hypotonia–cystinuria syndrome – HCS). Meanwhile, a large number of mutations in both genes have been reported, several of these variants were functionally analysed. Thereby, the aetiology of the disease as well as the physiological mechanisms of the renal trafficking of cystine could be deciphered. Key Concepts: Cystinuria is characterised by the defect transport of cystine, resulting in cystine stone formation. With SLC3A1 and SLC7A9, two disease causing genes have been identified. SLC3A1 and SLC7A9 encode the two subunits of the amino acid transporter b0,+. Mutations in SLC3A1 are predominantly associated with an autosomal recessive inheritance, whereas SLC7A9 mutations show an autosomal dominant inheritance with an incomplete penetrance. Homozygosity for large genomic deletions affecting both the SLC3A1 and the PREPL gene in 2p21 cause the hypotonia–cystinuria syndrome. Keywords: cystinuria; molecular Genetics; SLC3A1; SLC7A9; mutations; hypotonia-cystinuria syndrome
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Cystinuria: an inborn cause of urolithiasis
Orphanet journal of rare diseases, 2012Co-Authors: Thomas Eggermann, Andreas Venghaus, Klaus ZerresAbstract:Cystinuria (OMIM 220100) is an inborn congenital disorder characterised by a defective cystine metabolism resulting in the formation of cystine stones. Among the heterogeneous group of kidney stone diseases, cystinuria is the only disorder which is exclusively caused by gene mutations. So far, two genes responsible for cystinuria have been identified: SLC3A1 (chromosome 2p21) encodes the heavy subunit rBAT of a renal b0,+ transporter while SLC7A9 (chromosome 19q12) encodes its interacting light subunit b0,+AT. Mutations in SLC3A1 are generally associated with an autosomal-recessive mode of inheritance whereas SLC7A9 variants result in a broad clinical variability even within the same family. The detection rate for mutations in these genes is larger than 85%, but it is influenced by the ethnic origin of a patient and the pathophysiological significance of the mutations. In addition to isolated cystinuria, patients suffering from the hypotonia-cystinuria syndrome have been reported carrying deletions including at least the SLC3A1 and the PREPL genes in 2p21. By extensive molecular screening studies in large cohort of patients a broad spectrum of mutations could be identified, several of these variants were functionally analysed and thereby allowed insights in the pathology of the disease as well as in the renal trafficking of cystine and the dibasic amino acids. In our review we will summarize the current knowledge on the physiological and the genetic basis of cystinuria as an inborn cause of kidney stones, and the application of this knowledge in genetic testing strategies.
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Molecular Genetic Testing in Cystinuria
International Journal of Human Genetics, 2011Co-Authors: Thomas Eggermann, Sabrina Spengler, Julia Wirth, Sven LahmeAbstract:Cystinuria (OMIM 220100) is caused by the defective transport of cystine and the dibasic amino acids in the proximal renal tubule and in the epithelial cells of the gastrointestinal tract. We analysed a cohort of 26 unrelated cystinuria patients diagnosed on the basis of stone formation. Direct sequencing of all coding regions and exon-intron boundaries of the SLC3A1 and SLC7A9 genes allowed us to identify 26 different mutations in 23 out of the 26 patients, in total they accounted for 40 affected chromosomes. Three of the 26 are novel mutations, two in SLC3A1 and one in SLC7A9. Interestingly, two of our patients carried three mutations in SLC3A1 each, one patient was mixed heterozygous for SLC3A1 and SLC7A9 mutations. In summary, these findings expand the spectrum of SLC3A1 and SLC7A9 mutations and confirm the heterogeneity and complexity of cystinuria. If we assume an autosomal recessive inheritance of the disease, our detection rate was 88.5% and thereby relatively high in comparison to other studies. Nevertheless we have to consider that at least SLC7A9 mutations are often dominant, we therefore think that our effective detection rate is higher. Additionally, the broad pathophysiological consequences of SLC7A9 mutations make an individual prognosis and genetic counselling difficult.
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The population-specific distribution and frequencies of genomic variants in the SLC3A1 and SLC7A9 genes and their application in molecular genetic testing of cystinuria
Urological Research, 2004Co-Authors: Christa Schmidt, Udo Vester, Albrecht Hesse, Sven Lahme, Florian Lang, Klaus Zerres, Thomas EggermannAbstract:Cystinuria is a common inherited aminoaciduria resulting in nephrolithiasis. Mutations in two genes, SLC3A1 and SLC7A9 , have been identified in cystinuric patients. Considering the population-specific distribution of genetic variants in the SLC3A1 gene, we focused our study on mutations in SLC3A1 and SLC7A9 described more than once in the literature. We evaluated the usefulness of this restricted analysis as a diagnostic approach. Furthermore, the data obtained were used to estimate the frequency of heterozygote carriers of SLC3A1 mutations in the general European population. A total of 22 unclassified cystinuric patients were screened for genetic variants in four exons of both SLC3A1 and SLC7A9 in which the most common mutations have been identified. For screening, we used single strand conformation polymorphism analysis (SSCP), restriction assays, real-time PCR and direct sequencing. In total, we identified mutations in 17 of our 22 patients, including a new mutation (R365Q) as well as a novel polymorphism (c.1035G/A) within the SLC3A1 gene. An ethnic influence on the distribution of mutations was confirmed: T216M in SLC3A1 is the major mutation in south-eastern Europe, whereas M467T in SLC3A1 is mainly found in western Europe. A complex duplication in SLC3A1 is restricted to German patients. Generally, we could show that a stepwise analysis directed to the most common mutations in the two cystinuria genes is sufficient to detect variants in more than 75% of patients of European origin. The test consists of nine different PCR-based approaches and therefore represents a low-cost, reliable and timesaving diagnostic tool.
Maria Julia Calonge - One of the best experts on this subject based on the ideXlab platform.
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Localization, by linkage analysis, of the cystinuria type III gene to chromosome 19q13.1.
American journal of human genetics, 1997Co-Authors: Luigi Bisceglia, Maria Julia Calonge, Xavier Testar, Antonio Totaro, Lídia Feliubadaló, Salvatore Melchionda, Judith García, Michele Gallucci, Alberto Ponzone, Lepoldo ZelanteAbstract:Cystinuria is an autosomal recessive aminoaciduria in which three urinary phenotypes (I, II, and III) have been described. An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. Mutational and linkage analysis demonstrated the presence of genetic heterogeneity in which the SLC3A1 gene is responsible for type I cystinuria but not for type II or type III. In this study, we report the identification of the cystinuria type III locus on the long arm of chromosome 19 (19q13.1), obtained after a genomewide search. Pairwise linkage analysis in a series of type III or type II families previously excluded from linkage to the cystinuria type I locus (SLC3A1 gene) revealed a significant maximum LOD score (Z{sub max}) of 13.11 at a maximum recombination fraction ({theta}{sub max}) of .00, with marker D19S225. Multipoint linkage analysis performed with the use of additional markers from the region placed the cystinuria type III locus between D19S414 and D19S220. Preliminary data on type II families also seem to place the disease locus for this rare type of cystinuria at 19q13.1 (significant Z{sub max} = 3.11 at {theta}{sub max} of .00, with marker D19S225). 33 refs., 2 figs., 1 tab.
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Genetic heterogeneity in cystinuria: the SLC3A1 gene is linked to type I but not to type III cystinuria
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Maria Julia Calonge, Antonio Zorzano, Luigi Bisceglia, Leopoldo Zelante, V. Volpini, Ferran Rousaud, L. De Sanctis, Ercole Beccia, Xavier Testar, Xavier EstivillAbstract:Abstract Cystinuria is an autosomal recessive amino-aciduria where three urinary phenotypes have been described (I, II, and III). An amino acid transporter gene, SLC3A1 (formerly rBAT), was found to be responsible for this disorder. To assess whether mutations in SLC3A1 are involved in different cystinuria phenotypes, linkage with this gene and its nearest marker (D2S119) was analyzed in 22 families with type I and/or type III cystinuria. Linkage with heterogeneity was proved (alpha = 0.45; P 3.0 at theta = 0.00; alpha = 1), whereas types I/III and III/III were not linked. Our data suggest that type I cystinuria is due to mutations in the SLC3A1 gene, whereas another locus is responsible for type III. This result establishes genetic heterogeneity for cystinuria, classically considered as a multiallelic monogenic disease.