Human cationic amino acid transporter gene hCAT-2 is assigned to 8p22 but is not the causative gene in lysinuric protein intolerance

Lauteala, Tuija; Horelli‐Kuitunen, Nina; Closs, Ellen I.; Savontaus, Marja‐Liisa; Lukkarinen, Minna; Simell, Olli; Cunningham, James M.; Palotie, Aarno; Aula, Pertti

doi:10.1007/s004390050469

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…†Significant difference between HP-and LP-fed piglets at P Ͻ 0.05. ‡Significant difference between HP-and LP-fed piglets at P Ͻ 0.001. recent identification of two intestinal amino acid transporter genes opens up new possibilities for research into the mechanistic aspects of the different use rates (32,33). The third aim of the study was to examine the scale of the lysine metabolic response of the PDV to protein restriction and to investigate the extent to which intestinal lysine metabolism influenced its systemic availability.…”

Section: Discussionmentioning

confidence: 99%

Adaptive regulation of intestinal lysine metabolism

Goudoever

Stoll

Henry

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

136

102

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The metabolism of dietary essential amino acids by the gut has a direct effect on their systemic availability and potentially limits growth. We demonstrate that, in neonatal pigs bearing portal and arterial catheters and fed a diet containing 23% protein [high protein (HP) diet], more than half the intake of essential amino acids is metabolized by the portal-drained viscera (PDV). Intraduodenal or i.v. infusions of [U-13 C]-lysine were used to measure the appearance across and the use of the tracer by the PDV. In HP-fed pigs, lysine use by the PDV was derived almost entirely from the arterial input. In these animals, the small amount of dietary lysine used in first pass was oxidized almost entirely. Even so, intestinal lysine oxidation (24 mol͞kg per h) accounted for one-third of whole-body lysine oxidation (77 mol͞kg per h). Total lysine use by the PDV was not affected by low protein (LP) feeding (HP, 213 mol͞kg per h; LP,186 mol͞kg per h). In LP-fed pigs, the use of lysine by the PDV accounted for more than 75% of its intake. In contrast to HP feeding, both dietary and arterial lysines were used by the PDV of LP-fed pigs in nearly equal amounts. Intestinal lysine oxidation was suppressed completely. We conclude that the PDV are key organs with respect to amino acid metabolism and that the intestines use a disproportionately large amount of the dietary supply of amino acids during protein restriction.T he portal-drained viscera (PDV; the intestines, pancreas, spleen, and stomach) contribute between 20% and 35% of whole-body energy expenditure and protein synthesis, even though they contribute less than 6% of body weight (1-3). Dietary amino acid use by the intestine could have a substantial effect on their systemic availability and thereby regulate wholebody protein deposition. Studies in a number of mammalian species show that dietary essential amino acids (EAA) are directly used by the intestines for protein synthesis and other biosynthetic pathways (4-6).Futhermore, under high protein (HP) feeding conditions, intestinal energy production is derived largely from the oxidation of glutamate, glutamine, and aspartate (7-9). However, the oxidation of these substrates accounts for neither the total CO 2 production nor the production of alanine and ammonia by the PDV. The failure to account for the nitrogen outflow from the metabolism of glutamate, glutamine, and aspartate has led us to conclude that other amino acids, possibly including EAA, are oxidized in the PDV. There is evidence that leucine and methionine are oxidized by the enterocytes (10, 11), but we know of no detailed in vivo investigations of intestinal catabolism of other EAA. In this context, the oxidation of lysine would be of particular consequence, because this amino acid is nutritionally first limiting in cereal-based diets and milk (12).Investigations carried out 25 years ago were unable to find evidence for the presence of enzymes required for lysine catabolism in enterocytes (13,14), and it is generally held that lysine catabolism occurs prima...

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Section: Discussionmentioning

confidence: 99%

Adaptive regulation of intestinal lysine metabolism

Goudoever

Stoll

Henry

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

136

102

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“…In this work, recombination studies placed the locus between markers D14S72 and MYH7; the phenotype showed the highest linkage desequilibrium with marker T-cell receptor ␣ chain within this locus. Although functional criteria pointed to the cationic amino acid transporters (hCAT-1 and hCAT-2) as candidate genes, linkage studies, using flanking microsatellite markers, excluded both as the mutated gene in LPI (56). The human y ϩ LAT-1 gene is a good candidate for LPI: (i) 4F2hc is expressed at the basolateral membrane of proximal tubule epithelial cells in the kidney (57).…”

Section: Identification and Characterization Of Ymentioning

confidence: 99%

Identification and Characterization of a Membrane Protein (y+L Amino Acid Transporter-1) That Associates with 4F2hc to Encode the Amino Acid Transport Activity y+L

Torrents¹,

Estévez²,

Pineda³

et al. 1998

Journal of Biological Chemistry

310

247

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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, the Xenopus 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 Ϸ135-kDa, disulfide bond-dependent heterodimer with 4F2hc in oocytes, which upon reduction results in two protein bands of Ϸ85 kDa (i.e. 4F2hc) and Ϸ40 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 coexpressed 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 human y ؉ LAT-1 gene localizes at chromosome 14q11.2 (17cR Ϸ 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 coexpressed transport activity with 4F2hc, and its chromosomal location within the LPI locus, suggest y ؉ LAT-1 as a candidate gene for LPI.rBAT and 4F2hc are homologous proteins that induce amino acid transport in Xenopus oocytes (1, 2). These two proteins are slightly hydrophobic, which prompted the hypothesis that rBAT and 4F2hc are subunits or modulators of the corresponding amino acid transporter. This has been supported by several indirect observations: (i) rBAT and 4F2hc are involved in the induction of several activities in Xenopus oocytes (3-6); (ii) these two proteins can be immunodetected or immunoprecipitated as complexes of Ϸ125 kDa in the absence of reducing agents and as two proteins of Ϸ85 kDa (4F2hc or rBAT) and Ϸ40 kDa in the presence of reducing agents (7-9); and (iii) in oocytes, there is a dissociation between the expression of 4F2hc and rBAT at the plasma membrane and the induction of system y ϩ L and b 0,ϩ activity, respectively, indicating that this expression is limited by an endogenous factor (10, 11). We have recently provided new evidence that the amino acid transport system y ϩ L has a heterodimeric structure (11). Thus, we have shown that the y ϩ L activity induced in oocytes by a cysteineless mutant of human 4F2hc is also inactivated by membraneimpermeant thiol-specific ...

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“…19) and y + L (4F2hc/y + LAT-1 and 4F2hc/y + LAT-2 amino-acid transporters; refs 8,20) may explain the defect in LPI amino-acid transport activity. System y + amino-acid transporters, y + LAT-2 and 4F2hc were excluded as LPI genes by linkage studies, chromosomal location or tissue expression distribution [21][22][23] (SLC7A6, encoding y + LAT-2, localizes to chromosome 16; G25418, Whitehead Institute/MIT Center for Genome research).…”

mentioning

confidence: 99%

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

et al. 1999

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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.

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Human cationic amino acid transporter gene hCAT-2 is assigned to 8p22 but is not the causative gene in lysinuric protein intolerance

Cited by 9 publications

References 27 publications

Adaptive regulation of intestinal lysine metabolism

Adaptive regulation of intestinal lysine metabolism

Identification and Characterization of a Membrane Protein (y+L Amino Acid Transporter-1) That Associates with 4F2hc to Encode the Amino Acid Transport Activity y+L

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

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