Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene

Abstract

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; 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 baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts 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.

Basolateral LAT-2 Has a Major Role in the Transepithelial Flux of L-Cystine in the Renal Proximal Tubule Cell Line OK

“…The apical amino acid transporters responsible for this residual reabsorption are unknown. Dibasic amino acids leave renal epithelial cells across the basolateral domain via system y ϩ L. The main support for this is the fact that mutations in y ϩ LAT-1 (SLC7A7) cause lysinuric protein intolerance, a disease characterized by dibasic aminoaciduria (15,16). Transport activity reminiscent of system y ϩ L has been described in the basolateral membrane of rat enterocytes (33).…”

“…Second, y ϩ LAT-1 dimerizes with 4F2hc to form the amino acid transporter y ϩ L, which mediates the efflux of cationic amino acids coupled with the influx of neutral amino acids plus sodium (12)(13)(14). Mutations in y ϩ LAT-1 (SLC7A7) cause lysinuric protein intolerance (15,16), an inherited aminoaciduria due to defective dibasic amino acid efflux from the basolateral membrane of proximal tubule epithelial cells (17). Thus, systems b o,ϩ and y ϩ L explain the trans-epithelial transport of dibasic amino acids.…”

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

“…6 A founder effect mutation has been demonstrated only in Finland, where LPI patients share the same homozygous mutation, c.895-2A4T. 2,14 LPI patients show extreme variability in clinical presentation, and no genotypephenotype correlations have been defined. 18 This phenotypic variability and the lack of a specific clinical presentation have led to various misdiagnoses.…”

Urine Beta2-Microglobulin Is an Early Marker of Renal Involvement in LPI

“…It is caused by mutations in the gene SLC7A7 (solute carrier family 7, member 7) which encodes the y +LAT-1 protein, the catalytic light chain subunit of the heteromeric amino acid transporter. All Finnish patients share the same homozygous mutation, a substitution of T for A at cDNA position 1181-2 (Borsani et al 1999;Torrents et al 1998Torrents et al , 1999. LPI is more prevalent in Finland than elsewhere in the world, but several patients have been reported from, e.g.…”