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Gene Review

SLC7A7  -  solute carrier family 7 (amino acid...

Homo sapiens

Synonyms: LAT3, LPI, MOP-2, Monocyte amino acid permease 2, Solute carrier family 7 member 7, ...
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Disease relevance of SLC7A7

  • 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 [1].
  • Recently, the role of b(o,+)AT (SLC7A9) in cystinuria (non Type I) and the role of y(+)LAT-1 (SLC7A7) in lysinuric protein intolerance have been demonstrated [2].
  • Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mutation of the SLC7A7 gene characterized by renal failure, pulmonary alveolar proteinosis, lupus-like autoimmune symptoms and usually increased plasma citrulline [3].
  • On a normal diet, LPI patients present poor feeding, vomiting, diarrhoea, episodes of hyperammoniaemic coma and failure to thrive [4].
  • Recovery of spermatogenesis following treatment-induced azoospermia was significantly higher among the MOPP-2 patients (Mann-Whitney rank sum test, p = 0.001) [5].

Psychiatry related information on SLC7A7

  • LPIP activity was also found to be increased about two-fold in Alzheimer's disease when compared with normal or age-matched controls, while in globoidal-cell leukodystrophy (Krabbe's disease) it was similar to the normal controls [6].

High impact information on SLC7A7

  • We have identified two new transcripts (SLC7A8 and SLC7A7) homologous to amino acid transporters, highly expressed in kidney and mapping in the LPI critical region [4].
  • 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 [1].
  • The gene causing LPI was assigned using linkage analysis to chromosome 14q11.2 near the T-cell receptor alpha/delta chains locus, and a critical region has been defined [4].
  • LPI is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine [4].
  • Mutational analysis of both transcripts revealed that SLC7A7 (for solute carrier family 7, member 7) is mutated in LPI [4].

Chemical compound and disease context of SLC7A7

  • We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate [6].
  • In comparison with control specimens, morphometric measurements on trephine biopsies (initial staging procedure) disclosed a borderline or minimal increase in reticulin in CLL and moderate fibrosis in CB-CC and LPI, whereas HCL had the greatest increase in fibres [7].

Biological context of SLC7A7

  • Five novel SLC7A7 variants and y+L gene-expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance [8].
  • The human y+LAT-1 gene localizes at chromosome 14q11.2 (17cR approximately 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) [9].
  • The SLC7A7 gene comprises 11 exons, but the first two are not translated [10].
  • We also identified an alternative RNA splicing at the 5' untranslated region of the SLC7A7 mRNA in human peripheral blood leukocytes, cultured lymphoblasts, and fibroblasts [11].
  • The deduced amino acid sequence of LAT3 was identical to the gene product of POV1 reported as a prostate cancer-up-regulated gene whose function was not determined, whereas it did not exhibit significant similarity to already identified transporters [12].

Anatomical context of SLC7A7

  • In normal tissue, the gene-expression ratio of SLC7A6 to SLC7A7 was high in the brain, muscle, and cultured skin fibroblasts; low in the kidneys and small intestine; and at an intermediate level in peripheral blood leukocytes, the lungs, and cultured lymphoblasts [8].
  • Human y+LAT-1 mRNA is expressed in kidney >> peripheral blood leukocytes >> lung > placenta = spleen > small intestine [9].
  • By expression in Xenopus laevis oocytes and mammalian cells, we functionally analysed two SLC7A7 mutants, E36del and F152L, respectively, the former displaying a partial dominant-negative effect [13].
  • Different SLC7A7 mutations influenced the trafficking of y(+)LAT-1 in the cells differently, as the wild type and missense mutant fusion proteins localized to the plasma membrane, while the frameshift and nonsense mutants sequestered to the cytoplasmic membranes, never reaching the target areas of the cell [14].
  • By contrast, system B(0+), associated with system y(+)L (SLC3A2/SLC7A7 and SLC7A6), made a major contribution to the transport of cationic amino acids in pachytene spermatocytes and early spermatids [15].

Associations of SLC7A7 with chemical compounds

  • Lysinuric protein intolerance (LPI) is a rare autosomal recessive defect of dibasic amino acid transport caused by mutations in the SLC7A7 gene, resulting in an L-arginine deficiency [16].
  • Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive disorder characterized by defective transport of cationic amino acids lysine, arginine and ornithine [14].
  • When expressed in Xenopus oocytes, the encoded protein designated LAT3 (L-type amino acid transporter 3) transported neutral amino acids such as l-leucine, l-isoleucine, l-valine, and l-phenylalanine [12].
  • Although both the inhibitor of rabbit origin and of human origin are proteins produced by T cells and have similar inhibitory specificity, important differences were observed: LPI 1 is sensitive to boiling and the two inhibitors migrate differently upon electrophoresis in substrate-containing polyacrylamide gel [17].
  • Cholesterol and DOPC had little effect on DNA/DODAC binding while the anionic lipids LPI, DOPS, and DMPG inhibited complex formation [18].

Physical interactions of SLC7A7


Regulatory relationships of SLC7A7

  • This activity is also exerted by another complex composed of 4F2hc and y(+)LAT-2, the latter encoded by the SLC7A6 gene and more ubiquitously expressed than SLC7A7 [13].

Other interactions of SLC7A7

  • 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. A candidate gene for lysinuric protein intolerance [9].

Analytical, diagnostic and therapeutic context of SLC7A7

  • We successfully identified five novel SLC7A7 variants (S238F, S489P, 1630delC, 1673delG, and IVS3-IVS5del9.7kb) in Japanese patients with LPI by PCR amplification and direct DNA sequencing [8].
  • Northern blot analysis showed low and equal SLC7A7 mRNA levels in the control and LPI patient fibroblastoid and lymphoblast cells [10].
  • At the protein level, Western blotting and immunohistochemistry demonstrated an increased abundance of SNAT3 and reduced expression of the basolateral cationic amino acid/neutral amino acid exchanger subunit y(+)-LAT1 (SLC7A7) [20].
  • This is comparable to, or even less than, the cost of currently screened diseases in Japan. Therefore, we conclude that a mass screening program for LPI can be introduced effectively and economically into an area where an LPI cluster is located as the result of a founder mutation [21].


  1. Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene. Torrents, D., Mykkänen, J., Pineda, M., Feliubadaló, L., Estévez, R., de Cid, R., Sanjurjo, P., Zorzano, A., Nunes, V., Huoponen, K., Reinikainen, A., Simell, O., Savontaus, M.L., Aula, P., Palacín, M. Nat. Genet. (1999) [Pubmed]
  2. The molecular bases of cystinuria and lysinuric protein intolerance. Palacín, M., Borsani, G., Sebastio, G. Curr. Opin. Genet. Dev. (2001) [Pubmed]
  3. Increased NO production in lysinuric protein intolerance. Mannucci, L., Emma, F., Markert, M., Bachmann, C., Boulat, O., Carrozzo, R., Rizzoni, G., Dionisi-Vici, C. J. Inherit. Metab. Dis. (2005) [Pubmed]
  4. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Borsani, G., Bassi, M.T., Sperandeo, M.P., De Grandi, A., Buoninconti, A., Riboni, M., Manzoni, M., Incerti, B., Pepe, A., Andria, G., Ballabio, A., Sebastio, G. Nat. Genet. (1999) [Pubmed]
  5. Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy. da Cunha, M.F., Meistrich, M.L., Fuller, L.M., Cundiff, J.H., Hagemeister, F.B., Velasquez, W.S., McLaughlin, P., Riggs, S.A., Cabanillas, F.F., Salvador, P.G. J. Clin. Oncol. (1984) [Pubmed]
  6. Increased brain lysosomal pepstatin-insensitive proteinase activity in patients with neurodegenerative diseases. Junaid, M.A., Pullarkat, R.K. Neurosci. Lett. (1999) [Pubmed]
  7. Reticulin fibre content of bone marrow infiltrates of malignant non-Hodgkin's lymphomas (B-cell type, low malignancy)--a morphometric evaluation before and after therapy. Thiele, J., Langohr, J., Skorupka, M., Fischer, R. Virchows Archiv. A, Pathological anatomy and histopathology. (1990) [Pubmed]
  8. Five novel SLC7A7 variants and y+L gene-expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance. Shoji, Y., Noguchi, A., Shoji, Y., Matsumori, M., Takasago, Y., Takayanagi, M., Yoshida, Y., Ihara, K., Hara, T., Yamaguchi, S., Yoshino, M., Kaji, M., Yamamoto, S., Nakai, A., Koizumi, A., Hokezu, Y., Nagamatsu, K., Mikami, H., Kitajima, I., Takada, G. Hum. Mutat. (2002) [Pubmed]
  9. 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. A candidate gene for lysinuric protein intolerance. Torrents, D., Estévez, R., Pineda, M., Fernández, E., Lloberas, J., Shi, Y.B., Zorzano, A., Palacín, M. J. Biol. Chem. (1998) [Pubmed]
  10. Promoter analysis of the human SLC7A7 gene encoding y+L amino acid transporter-1 (y+LAT-1). Mykkänen, J., Toivonen, M., Kleemola, M., Savontaus, M.L., Simell, O., Aula, P., Huoponen, K. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  11. SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families. Noguchi, A., Shoji, Y., Koizumi, A., Takahashi, T., Matsumori, M., Kayo, T., Ohata, T., Wada, Y., Yoshimura, I., Maisawa, S., Konishi, M., Takasago, Y., Takada, G. Hum. Mutat. (2000) [Pubmed]
  12. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. Babu, E., Kanai, Y., Chairoungdua, A., Kim, d.o. .K., Iribe, Y., Tangtrongsup, S., Jutabha, P., Li, Y., Ahmed, N., Sakamoto, S., Anzai, N., Nagamori, S., Endou, H. J. Biol. Chem. (2003) [Pubmed]
  13. A y(+)LAT-1 mutant protein interferes with y(+)LAT-2 activity: implications for the molecular pathogenesis of lysinuric protein intolerance. Sperandeo, M.P., Paladino, S., Maiuri, L., Maroupulos, G.D., Zurzolo, C., Taglialatela, M., Andria, G., Sebastio, G. Eur. J. Hum. Genet. (2005) [Pubmed]
  14. Expression of normal and mutant GFP-tagged y(+)L amino acid transporter-1 in mammalian cells. Toivonen, M., Mykkänen, J., Aula, P., Simell, O., Savontaus, M.L., Huoponen, K. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  15. Multiple pathways for cationic amino Acid transport in rat seminiferous tubule cells. Cérec, V., Piquet-Pellorce, C., Aly, H.A., Touzalin, A.M., Jégou, B., Bauché, F. Biol. Reprod. (2007) [Pubmed]
  16. Vascular endothelial dysfunction resulting from L-arginine deficiency in a patient with lysinuric protein intolerance. Kamada, Y., Nagaretani, H., Tamura, S., Ohama, T., Maruyama, T., Hiraoka, H., Yamashita, S., Yamada, A., Kiso, S., Inui, Y., Ito, N., Kayanoki, Y., Kawata, S., Matsuzawa, Y. J. Clin. Invest. (2001) [Pubmed]
  17. A serine proteinase inhibitor produced by an HTLV I virus-transformed human T lymphocyte line. Ganea, D., Cearlock, D., Minowada, J., Dray, S. J. Immunol. (1987) [Pubmed]
  18. Cationic lipid binding to DNA: characterization of complex formation. Wong, F.M., Reimer, D.L., Bally, M.B. Biochemistry (1996) [Pubmed]
  19. Cystinuria calls for heteromultimeric amino acid transporters. Palacín, M., Estévez, R., Zorzano, A. Curr. Opin. Cell Biol. (1998) [Pubmed]
  20. Regulation of renal amino acid transporters during metabolic acidosis. Moret, C., Dave, M.H., Schulz, N., Jiang, J.X., Verrey, F., Wagner, C.A. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  21. Evaluation of a mass screening program for lysinuric protein intolerance in the northern part of Japan. Koizumi, A., Matsuura, N., Inoue, S., Utsunomiya, M., Nozaki, J., Inoue, K., Takasago, Y. Genet. Test. (2003) [Pubmed]
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