Abstract
Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population1; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the basolateral membrane of epithelial cells in small intestine and in renal tubules2,3,4 and in plasma membrane of cultured skin fibroblasts5 from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.
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Acknowledgements
We thank J. García for technical assistance; E. Fernández, N. Reig and J. Purroy for helpful discussions; C. Busquets for Spanish control DNA samples; and R. Rycroft for editorial help. This research was supported in part by Dirección General de Investigación Científica y Técnica research grant PM96/0060, EU BIOMED 2 Grant BMH4CT98-3514, Fundació La Marató-TV3 research grant 981930, and Generalitat de Catalunya grants 1997 SGR 121 and 1997 SGR 00085 from Spain and by The Foundation for Pediatric Research from Finland and The Academy of Finland. D.T. is a recipient of a fellowship from the Ministerio de Educación y Cultura (Spain), and M.P., L.F. and R.E. are recipients of fellowships from the Comissió Interdepartamental de Recerca i Tecnologia (Catalonia, Spain).
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Department of Pediatrics, Turku University Central Hospital, 20520 Turku, Finland.
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Torrents, D., Mykkänen, J., Pineda, M. et al. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Nat Genet 21, 293–296 (1999). https://doi.org/10.1038/6809
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DOI: https://doi.org/10.1038/6809
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