Human Molecular Genetics, 2000, Vol. 9, No. 3 431-438
© 2000 Oxford University Press
Functional analysis of novel mutations in y+LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI)
1Department of Medical Genetics, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, 2Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avda. Diagonal 645, 08028 Barcelona, Spain, 3Department of Neuropediatrics, Hospital Virgen del camino, Pamplona, Spain, 4Department of Biology, University of Turku, FIN-20500 Turku, Finland, 5Department of Pediatrics, University of Turku, FIN-20520 Turku, Finland, 6Laboratory Department of Helsinki University Hospital and Department of Clinical Chemistry, University of Helsinki, FIN-00014 Helsinki, Finland and 7Department of Medical Genetics, Haartman Institute, University of Helsinki, FIN 00014 Helsinki, Finland
Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive disorder characterized by defective transport of the cationic amino acids lysine, arginine and ornithine at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules, and by hyperammonemia after high-protein meals. LPI is caused by mutations in the SLC7A7 (solute carrier family 7, member 7) gene encoding y+LAT-1 (y+L amino acid transporter-1), which co-induces together with 4F2 heavy chain (4F2hc) system y+L in Xenopus oocytes. All Finnish LPI patients share the same founder mutation 1181-2A
T (LPIFin) not found in LPI patients elsewhere. Mutation screening of 20 non-Finnish LPI patients revealed 10 novel mutations: four deletions, two missense mutations, two nonsense mutations, a splice site mutation and a tandem duplication. Five LPI mutations (L334R, G54V, 1291delCTTT, 1548delC and LPIFin) were studied functionally. All mutant proteins failed to co-induce amino acid transport activity when expressed with 4F2hc in Xenopus oocytes. Immunostaining experiments revealed that frameshift mutants 1291delCTTT, 1548delC and LPIFin remained intracellular on expression with 4F2hc. In contrast, the missense mutants L334R and G54V reached the oocyte plasma membrane when co-expressed with 4F2hc, demonstrating that they are transport-inactivating mutations. This finding, together with the strong degree of conservation among all members of this family of amino acid transporters, indicates that residues L334 and G54 play a crucial role in the function of the y+LAT-1 transporter.
+ These authors contributed equally to this work
§ To whom correspondence should be addressed. Tel: +358 2 333 7235; Fax: +358 2 333 7300; Email: jmykkane@utu.fi
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