Abstract
The Na+-dependent amino acid transporter named ATB0 was previously found to be located in 19q13.3 by fluorescence in situ hybridisation. Genetic heterogeneity in the 19q13.2-13.4 region, syntenic to the Cystic Fibrosis Modulator Locus 1 (CFM1) in mouse, seemed to be associated to the intestinal phenotypic variation of cystic fibrosis (CF). We performed fine chromosomal mapping of ATB0 on radiation hybrid (RH) panels G3 and TNG. Based on the most accurate location results from TNG-RH panel, mapping analysis evidenced that ATB0 is localised between STS SHGC-13875 (D19S995) and STS SHGC-6138 in 19q13.3, that corresponds with the immediately telomeric/distal segment of the strongest linkage region within the human CFM1 (hCFM1) syntenic region. Regarding to the genomic structure and exon organisation, our results show that the ATB0 gene is organised into eight exons. The knowledge of the genomic structure allowed us to perform an exhaustive mutational analysis of the gene. Evaluation of the possible implication of ATB0 in the intestinal phenotype of CF was performed on the basis of the functional characteristics of the encoded protein, its apparent relevance to meconium ileus (MI) and position in relation to the hCFM1 syntenic region. We have analysed this gene in samples from CF patients with and without MI. Several sequence variations in the ATB0 gene were identified, although none of them seemed to be related to the intestinal phenotype of CF. Even though no particular allele or haplotype in ATB0 appears to be associated to CF-MI disease, new SNPs identified should be useful in segregation and linkage disequilibrium analyses in families affected by other disorders caused by the impairment of neutral amino acid transport.
Similar content being viewed by others
Article PDF
References
Christensen HN . Role of amino acid transport and countertransport in nutrition and metabolism Physiol Rev 1990 70: 43–77
Stevens BR . Vertebrate intestine apical membrane mechanisms of organic nutrient transport Am J Physiol 1992 263: R458–R463
Kekuda R, Prasad PD, Fei Y-J, et al. Cloning of the sodium-dependent, broad-scope, neutral amino acid transporter B0 form a human placental choriocarcinoma cell line J Biol Chem 1996 271: 18657–18661
Jones EMC, Menzel S, Espinosa R, Le Beau MM, Bell GI, Takeda J . Localisation of the gene encoding a neutral amino acid transporter-like protein to human chromosome band 19q13.3 and characterisation of a simple sequence repeat DNA polymorphism Genomics 1994 23: 490–491
Kekuda R, Torres-Zamorano V, Fei YJ, et al. Molecular and functional characterization of intestinal Na(+)-dependent neutral amino acid transporter B0 Am J Physiol 1997 272: 6 Pt 1 G1463–1472
Rasko JE, Battini JL, Gottschalk RJ, Mazo I, Miller AD . The RD114/simian type D retrovirus receptor is a neutral amino acid transporter Proc Natl Acad Sci USA 1999 96: 2129–2134
Palacín M, Estevez R, Bertrán J, Zorzano A . Mammalian plasma membrane amino acid transporters Physiol Rev 1998 78: 969–1054
Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis Science 1989 245: 1073–1080
Boucher RC, Stutts MJ, Knowles MR, Cantley L, Gatzy JT . Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation J Clin Invest 1986 78: 1245–1252
Schwiebert EM, Benos DJ, Egan ME, Stutts MJ, Guggino WB . CFTR is a conductance regulator as well as a chloride channel Physiol Rev 1999 79: S145–S166
Mall M, Bleich M, Kuehr J, Brandis M, Greger R, Kunzelmann K . CFTR-mediated inhibition of epithelial Na+ conductance in human colon in defective cystic fibrosis Am J Physiol 1999 277: G709–G716
Wu JV, Joo NS Krouse M, Wine JJ . CFTR gating requires cytosolic electrolytes J Biol Chem 2001 276: 6473–6478
Rozmahel R, Wilschanski M, Matin A, et al. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor Nat Genet 1996 12: 280–287
Zielenski J, Corey M, Rozmahel R, et al. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13 Nat Genet 1999 22: 128–129
Stewart EA, McKusick KB, Aggarwal A, et al. An STS-based radiation hybrid map of the human genome Genome Res 1997 7: 422–433
Kunkel LM, Smith KD, Boyer SH, et al. Analysis of human Y-chromosome specific reiterated DNA in chromosome variants Proc Natl Acad Sci USA 1977 74: 1245–1249
Olivier M, Aggarwal A, Allen J et al. A High-Resolution Radiation Hybrid Map of the Human Genome Draft Sequence Science 2001 291: 1298–1302
Arriza JL, Eliasof S, Kavanaugh MP, Amara SG . Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance Proc Natl Acad Sci USA 1997 94: 4155–4160
Acknowledgements
We are indebted to the patients who participated in this study. We thank Dr. Anna Aviñó for primer synthesis, Dr Manuel Palacín for his helpful discussion, Esther Villén and Dr Victor Volpini for their advice on statistical analysis, Nuria Andreu for her help with RH mapping and Helena Kruyer for her help with the manuscript. This work was supported by grants from FIS (99/0654), Fundació La Marató TV3 (980410) and Institut Catalá de la Salut. S Larriba is supported by Fundació La Marató TV3 and L Sumoy by EU Biomed Proyect BMH4-CT97-2284 to X Estivill.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Larriba, S., Sumoy, L., Ramos, M. et al. ATB0/SLC1A5 gene. Fine localisation and exclusion of association with the intestinal phenotype of cystic fibrosis. Eur J Hum Genet 9, 860–866 (2001). https://doi.org/10.1038/sj.ejhg.5200726
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200726
Keywords
This article is cited by
-
Diet evolution of carnivorous and herbivorous mammals in Laurasiatheria
BMC Ecology and Evolution (2022)
-
Hierarchical fine mapping of the cystic fibrosis modifier locus on 19q13 identifies an association with two elements near the genes CEACAM3 and CEACAM6
Human Genetics (2010)