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Pilar Mur, Marta Pineda,
Atocha Romero,
Jesús Del Valle,
Ester Borràs,
Alicia Canal,
Matilde Navarro,
Joan Brunet,
Daniel Rueda,
Teresa Ramón Y Cajal,
Conxi Lázaro,
Trinidad Caldés,
Ignacio Blanco,
José Luis Soto,
Gabriel Capellá
[show abstract]
[hide abstract]
ABSTRACT: Germline deletions at the 3' end of EPCAM have been involved in the etiology of Lynch syndrome. The aim of this study was to characterize at the molecular level Spanish families harboring EPCAM deletions. Non-commercial MLPA probes and long-range PCR amplification were used to characterize each deletion. Haplotyping was performed by analyzing 8 microsatellite markers and 5 MSH2 SNPs. Methylation of MSH2 was analyzed by Methylation Specific-MLPA. Tumors diagnosed in 7 Spanish families harboring EPCAM deletions were almost exclusively colorectal. Mosaicism in MSH2 methylation was observed in EPCAM deletion carrier samples, being average methylation levels higher in normal colon and colorectal tumors (27.6 and 31.1%), than in lymphocytes and oral mucosa (1.1 and 0.7%). Three families shared the deletion c.858+2568_*4596del, with a common haplotype comprising 9.9Mb. In two families the novel EPCAM deletion c.858+2488_*7469del was identified. The present study provides knowledge on the clinical and molecular characteristics of mosaic MSH2 epimutations. The identification of an EPCAM founder mutation has useful implications for the molecular diagnosis of Lynch syndrome in Spain.
Clinical Genetics 03/2013; · 3.13 Impact Factor
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Lídia Feliubadaló,
Adriana Lopez-Doriga,
Ester Castellsagué,
Jesús Del Valle,
Mireia Menéndez,
Eva Tornero,
Eva Montes,
Raquel Cuesta,
Carolina Gómez,
Olga Campos, Marta Pineda,
Sara González,
Victor Moreno,
Joan Brunet,
Ignacio Blanco,
Eduard Serra,
Gabriel Capellá,
Conxi Lázaro
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Nuria Seguí, Marta Pineda,
Elisabet Guinó,
Ester Borràs,
Matilde Navarro,
Fernando Bellido,
Victor Moreno,
Conxi Lázaro,
Ignacio Blanco,
Gabriel Capellá,
Laura Valle
[show abstract]
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ABSTRACT: Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.
PLoS ONE 01/2013; 8(4):e61286. · 4.09 Impact Factor
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Lídia Feliubadaló,
Adriana Lopez-Doriga,
Ester Castellsagué,
Jesús Del Valle,
Mireia Menéndez,
Eva Tornero,
Eva Montes,
Raquel Cuesta,
Carolina Gómez,
Olga Campos, Marta Pineda,
Sara González,
Victor Moreno,
Joan Brunet,
Ignacio Blanco,
Eduard Serra,
Gabriel Capellá,
Conxi Lázaro
[show abstract]
[hide abstract]
ABSTRACT: Next-generation sequencing (NGS) is changing genetic diagnosis due to its huge sequencing capacity and cost-effectiveness. The aim of this study was to develop an NGS-based workflow for routine diagnostics for hereditary breast and ovarian cancer syndrome (HBOCS), to improve genetic testing for BRCA1 and BRCA2. A NGS-based workflow was designed using BRCA MASTR kit amplicon libraries followed by GS Junior pyrosequencing. Data analysis combined Variant Identification Pipeline freely available software and ad hoc R scripts, including a cascade of filters to generate coverage and variant calling reports. A BRCA homopolymer assay was performed in parallel. A research scheme was designed in two parts. A Training Set of 28 DNA samples containing 23 unique pathogenic mutations and 213 other variants (33 unique) was used. The workflow was validated in a set of 14 samples from HBOCS families in parallel with the current diagnostic workflow (Validation Set). The NGS-based workflow developed permitted the identification of all pathogenic mutations and genetic variants, including those located in or close to homopolymers. The use of NGS for detecting copy-number alterations was also investigated. The workflow meets the sensitivity and specificity requirements for the genetic diagnosis of HBOCS and improves on the cost-effectiveness of current approaches.European Journal of Human Genetics advance online publication, 19 December 2012; doi:10.1038/ejhg.2012.270.
European journal of human genetics: EJHG 12/2012; · 3.56 Impact Factor
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Fernando Bellido,
Elisabet Guinó,
Shantie Jagmohan-Changur,
Nuria Seguí, Marta Pineda,
Matilde Navarro,
Conxi Lázaro,
Ignacio Blanco,
Hans Fa Vasen,
Victor Moreno,
Gabriel Capellá,
Juul T Wijnen,
Laura Valle
[show abstract]
[hide abstract]
ABSTRACT: Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative risk(LSca<45_AA)=2.90; 95% confidence interval=1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.European Journal of Human Genetics advance online publication, 5 September 2012; doi:10.1038/ejhg.2012.204.
European journal of human genetics: EJHG 09/2012; · 3.56 Impact Factor
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Marta Pineda,
Pilar Mur,
María Dolores Iniesta,
Ester Borràs,
Olga Campos,
Gardenia Vargas,
Sílvia Iglesias,
Anna Fernández,
Stephen B Gruber,
Conxi Lázaro,
Joan Brunet,
Matilde Navarro,
Ignacio Blanco,
Gabriel Capellá
[show abstract]
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ABSTRACT: Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.European Journal of Human Genetics advance online publication, 4 July 2012; doi:10.1038/ejhg.2012.136.
European journal of human genetics: EJHG 07/2012; · 3.56 Impact Factor
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Ester Borràs, Marta Pineda,
Angela Brieger,
Inga Hinrichsen,
Carolina Gómez,
Matilde Navarro,
Judit Balmaña,
Teresa Ramón Y Cajal,
Asunción Torres,
Joan Brunet,
Ignacio Blanco,
Guido Plotz,
Conxi Lázaro,
Gabriel Capellá
[show abstract]
[hide abstract]
ABSTRACT: Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244G>A (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families. Hum Mutat 33:1576-1588, 2012. © 2012 Wiley Periodicals, Inc.
Human Mutation 06/2012; 33(11):1576-88. · 5.69 Impact Factor
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Mireia Gausachs,
Pilar Mur,
Julieta Corral, Marta Pineda,
Sara González,
Llúcia Benito,
Mireia Menéndez,
Josep Alfons Espinàs,
Joan Brunet,
María Dolores Iniesta,
Stephen B Gruber,
Conxi Lázaro,
Ignacio Blanco,
Gabriel Capellá
[show abstract]
[hide abstract]
ABSTRACT: The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.
European journal of human genetics: EJHG 01/2012; 20(7):762-8. · 3.56 Impact Factor
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Lucia Pérez-Cabornero,
Ester Borrás Flores,
Mar Infante Sanz,
Eladio Velasco Sampedro,
Alberto Acedo Becares,
Enrique Lastra Aras,
Jorge Cuevas González, Marta Pineda Riu,
Teresa Ramón y Cajal Asensio,
Gabriel Capellá Munar,
Cristina Miner Pino,
Mercedes Durán Domínguez
[show abstract]
[hide abstract]
ABSTRACT: It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype-phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer-related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns.
Cancer Prevention Research 07/2011; 4(10):1546-55. · 4.91 Impact Factor
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Ester Borràs, Marta Pineda,
Ignacio Blanco,
Ethan M Jewett,
Fei Wang,
Alex Teulé,
Trinidad Caldés,
Miguel Urioste,
Cristina Martínez-Bouzas,
Joan Brunet, [......],
Sergi Castellví-Bel,
Angel Alonso,
Angel Lanas,
Sara González,
Víctor Moreno,
Stephen B Gruber,
Noah A Rosenberg,
Bhramar Mukherjee,
Conxi Lázaro,
Gabriel Capellá
[show abstract]
[hide abstract]
ABSTRACT: The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.
Cancer Research 10/2010; 70(19):7379-91. · 7.86 Impact Factor
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[show abstract]
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ABSTRACT: There are two major hereditary colorectal cancer syndromes: Adenomatous Polyposis, secondary to APC germline alterations (FAP, Familial Adenomatous Polyposis) or secondary to MUTYH germline alterations (MAP, MUTYH associated Polyposis), and Lynch syndrome, associated with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2). The elucidation of their genetic basis has depicted an increasingly complex picture that has lead to the implementation of complex diagnostic algorithms that include both tumor profiling and germline analyses. A variety of techniques at the DNA, RNA and protein level are used to screen for molecular alterations both in tumor biopsies (microsatellite instability analysis, mismatch repair protein immunohistochemistry, BRAF-Val600Glu detection and MLH1 promoter hypermethylation analysis) and in the germline (point mutation screening, copy number assessment). Also functional tests are more often used to characterize variants of unknown significance. Methodological issues associated with the techniques analyzed, as well as the algorithms used, are discussed.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2009; 693(1-2):19-31. · 2.85 Impact Factor
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[show abstract]
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ABSTRACT: The possible function of the maize transmembrane protein TM20 in hormone transport has been investigated using immunological methods and by microinjection of TM20 cRNA in Xenopus oocytes. The existence of a similar gene in rice indicates that the overall structure of the deduced protein is conserved between these two cereals. An antibody raised against a conserved motif, in a loop between two transmembrane domains, locates the protein (TM20) in differentiating provascular cells in maize embryo. The protein has a polarized distribution within the cell in the most differentiated stages of development. Xenopus laevis oocytes microinjected with TM20 appear to modify transport activities across the plasma membrane. These results are discussed in relation to other transport proteins that influence plant development.
Planta 10/2005; 222(1):80-90. · 3.00 Impact Factor
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ABSTRACT: Heteromeric amino acid transporters (HATs) are composed of a heavy (SLC3 family) and a light (SLC7 family) subunit. Mutations in system b(0,+) (rBAT-b(0,+)AT) and in system y(+)L (4F2hc-y(+)LAT1) cause the primary inherited aminoacidurias (PIAs) cystinuria and lysinuric protein intolerance, respectively. Recent developments [including the identification of the first Hartnup disorder gene (B0AT1; SLC6A19)] and knockout mouse models have begun to reveal the basis of renal and intestinal reabsorption of amino acids in mammals.
Physiology (Bethesda, Md.) 05/2005; 20:112-24. · 7.95 Impact Factor
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Marta Pineda,
Mariona Font,
Maria Teresa Bassi,
Marta Manzoni,
Giuseppe Borsani,
Valeria Marigo,
Esperanza Fernández,
Rafael Martín del Río,
Jesús Purroy,
Antonio Zorzano,
Virginia Nunes,
Manuel Palacín
[show abstract]
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ABSTRACT: The human amino acid transporter asc-1 (SLC7A10) exhibits substrate selectivity for small neutral amino acids, including cysteine, is expressed in kidney, is located close to the cystinuria B gene and presents sequence variants (e.g., E112D) in some cystinuria patients. We have cloned human asc-1, assessed its transport characteristics, localized its expression in kidney, searched for mutations in cystinuria patients, and tested the transport function of variant E112D.
We used an EST-based homology cloning strategy. Transport characteristics of asc-1 were assessed by coexpression with 4F2hc in Xenopus oocytes and HeLa cells. Localization of asc-1 mRNA in kidney was assessed by in situ hybridization. Exons and intron-exon boundaries were polymerase chain reaction (PCR)-amplified from blood cell DNA and mutational screening was performed by single-stranded conformational polymorphism (SSCP).
Asc-1 reaches the plasma membrane in HeLa cells, unlike in oocytes, most probably by interaction with endogenous 4F2hc and presents similar transport characteristics to those in oocytes coexpressing asc-1/4F2hc. Asc-1 mediates a substantial efflux of alanine in a facilitated diffusion mode of transport. Expression of asc-1 mRNA localized to Henle's loop, distal tubules, and collecting ducts. Finally, SLC7A10 polymorphisms were identified in cystinuria probands and the SLC7A10 sequence variant E112D showed full transport activity.
The lack of expression of asc-1 in the proximal tubule indicates that it plays no role in the bulk of renal reabsorption of amino acids. No mutations causing cystinuria have been found in SLC7A10. The facilitated diffusion mode of transport and the expression in distal nephron suggest a role for asc-1 in osmotic adaptation.
Kidney International 11/2004; 66(4):1453-64. · 6.61 Impact Factor
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Marta Pineda,
Carsten A Wagner,
Angelika Bröer,
Paul A Stehberger,
Simone Kaltenbach,
Josep Ll Gelpí,
Rafael Martín Del Río,
Antonio Zorzano,
Manuel Palacín,
Florian Lang,
Stefan Bröer
[show abstract]
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ABSTRACT: Apical reabsorption of dibasic amino acids and cystine in kidney is mediated by the heteromeric amino acid antiporter rBAT/b(0,+)AT (system b(0,+)). Mutations in rBAT cause cystinuria type A, whereas mutations in b(0,+)AT cause cystinuria type B. b(0,+)AT is the catalytic subunit, whereas it is believed that rBAT helps the routing of the rBAT/b(0,+)AT heterodimeric complex to the plasma membrane. In the present study, we have functionally characterized the cystinuria-specific R365W (Arg(365)-->Trp) mutation of human rBAT, which in addition to a trafficking defect, alters functional properties of the b(0,+) transporter. In oocytes, where human rBAT interacts with the endogenous b(0,+)AT subunit to form an active transporter, the rBAT(R365W) mutation caused a defect of arginine efflux without altering arginine influx or apparent affinities for intracellular or extracellular arginine. Transport of lysine or leucine remained unaffected. In HeLa cells, functional expression of rBAT(R365W)/b(0,+)AT was observed only at the permissive temperature of 33 degrees C. Under these conditions, the mutated transporter showed 50% reduction of arginine influx and a similar decreased accumulation of dibasic amino acids. Efflux of arginine through the rBAT(R365W)/b(0,+)AT holotransporter was completely abolished. This supports a two-translocation-pathway model for antiporter b(0,+), in which the efflux pathway in the rBAT(R365W)/b(0,+)AT holotransporter is defective for arginine translocation or dissociation. This is the first direct evidence that mutations in rBAT may modify transport properties of system b(0,+).
Biochemical Journal 03/2004; 377(Pt 3):665-74. · 4.90 Impact Factor
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[show abstract]
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ABSTRACT: We have identified a new human cDNA (y+L amino acid transporter-1 (y+LAT-1)) that induces system y+L transport activity with 4F2hc (the surface antigen 4F2 heavy chain) in oocytes. Human y+LAT-1 is a new member of a family of polytopic transmembrane proteins that are homologous to the yeast high affinity methionine
permease MUP1. Other members of this family, theXenopus laevis IU12 and the human KIAA0245 cDNAs, also co-express amino acid transport activity with 4F2hc in oocytes, with characteristics
that are compatible with those of systems L and y+L, respectively. y+LAT-1 protein forms a ≈135-kDa, disulfide bond-dependent heterodimer with 4F2hc in oocytes, which upon reduction results in
two protein bands of ≈85 kDa (i.e. 4F2hc) and ≈40 kDa (y+LAT-1). Mutation of the human 4F2hc residue cysteine 109 (Cys-109) to serine abolishes the formation of this heterodimer and
drastically reduces the co-expressed transport activity. These data suggest that y+LAT-1 and other members of this family are different 4F2 light chain subunits, which associated with 4F2hc, constitute different
amino acid transporters. Human y+LAT-1 mRNA is expressed in kidney ≫ peripheral blood leukocytes ≫ lung > placenta = spleen > small intestine. The humany+LAT-1 gene localizes at chromosome 14q11.2 (17cR ≈ 374 kb from D14S1350), within the lysinuric protein intolerance (LPI) locus
(Lauteala, T., Sistonen, P., Savontaus, M. L., Mykkanen, J., Simell, J., Lukkarinen, M., Simmell, O., and Aula, P. (1997)
Am. J. Hum. Genet. 60, 1479–1486). LPI is an inherited autosomal disease characterized by a defective dibasic amino acid transport in kidney,
intestine, and other tissues. The pattern of expression of human y+LAT-1, its co-expressed transport activity with 4F2hc, and its chromosomal location within the LPI locus, suggest y+LAT-1 as a candidate gene for LPI.
Journal of Biological Chemistry 12/1998; 273(49):32437-32445. · 4.77 Impact Factor
