Alternative titles; symbols
HGNC Approved Gene Symbol: SLC7A7
SNOMEDCT: 303852004;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38) : 14:22,773,222-22,819,791 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Lysinuric protein intolerance | 222700 | Autosomal recessive | 3 |
The SLC7A7 gene encodes the light subunit of a cationic amino acid transporter. Together with the heavy chain, 4F2hc (SLC3A2; 158070), the SLC7A7 protein forms a functional heterodimeric transporter on the basolateral cell membrane of epithelial cells that transfers lysine, arginine, and ornithine from the cell to the extracellular space (Torrents et al., 1998; Puomila et al., 2007).
Torrents et al. (1998) identified a human cDNA, designated SLC7A7, corresponding to the y(+)L-type amino acid transporter 1 subunit. The SLC7A7 gene encodes a deduced 511-residue protein with a molecular mass of 56 kD that contains 12 transmembrane domains. The protein sequence shows 81% homology to the opossum protein. Northern blot analysis identified a 2.4-kb mRNA transcript expressed in kidney, peripheral blood leukocytes, lung, placenta, spleen, and small intestine. SLC7A7 associated with SLC3A2 to form a functional 135-kD heterodimer linked by a disulfide bridge involving cysteine 109 of SLC3A2. Human SLC7A7 is mainly expressed at the basolateral membrane of epithelial cells in the renal tubules and small intestine.
Noguchi et al. (2000) identified an alternatively spliced isoform of SLC7A7 that lacked exon 2, which is a noncoding exon.
Puomila et al. (2007) characterized 2 functional promoters of the SLC7A7 gene: an 'upstream' promoter in front of exon 1 that appeared to be active in brain, and a 'downstream' TATA-box-containing promoter in front of exon 2 that was active in kidney, small intestine, and brain. Puomila et al. (2007) suggested that these promoters may play a role in tissue-specific regulation of SLC7A7 gene expression.
The SLC7A7 gene contains 11 exons and spans 47 kb of genomic DNA in the antisense strand. The codon for translation initiation is in exon 3 (Noguchi et al., 2000; Sperandeo et al., 2008).
Torrents et al. (1998) mapped the SLC7A7 gene to chromosome 14q11.2.
In 31 Finnish patients with lysinuric protein intolerance (LPI; 222700), Torrents et al. (1999) identified homozygosity for a founder mutation in the SLC7A7 gene (603593.0001). Borsani et al. (1999) defined the Finnish mutation as a splice acceptor change resulting in a frameshift and premature translation termination.
Torrents et al. (1999) also reported a Spanish LPI patient who was compound heterozygous for 2 mutations (603593.0005; 603593.0006) in the SLC7A7 gene.
In 5 Italian patients with LPI, Borsani et al. (1999) found either an insertion or a deletion in the coding sequence of the SLC7A7 gene (603593.0002; 603593.0003).
Sperandeo et al. (2000) identified mutations in the SLC7A7 gene (see, e.g., 603593.0004) in Italian, Tunisian, and Japanese LPI patients. All mutant alleles in 11 unrelated families were characterized, and 8 novel mutations were detected.
Mykkanen et al. (2000) performed mutation screening of 20 non-Finnish LPI patients and found 10 novel mutations: 4 deletions, 2 missense mutations, 2 nonsense mutations, a splice site mutation, and a tandem duplication. Functional studies of 5 LPI mutations showed that all mutant proteins failed to induce amino acid transport activity when expressed with 4F2hc in Xenopus oocytes.
In affected members of 2 Japanese LPI families, Noguchi et al. (2000) identified a homozygous mutation in the SLC7A7 gene (R410X; 603593.0008).
Shoji et al. (2002) identified 5 novel SLC7A7 variants in Japanese patients with LPI by PCR amplification and direct DNA sequencing.
Sperandeo et al. (2008) identified 9 novel mutations in the SLC7A7 gene, and noted that a total of 43 different mutations had been identified in over 100 patients with LPI. Mutations were spread throughout the gene with no apparent genotype/phenotype correlations.
Font-Llitjos et al. (2009) identified 11 mutations in the SLC7A7, including 7 novel mutations, in 11 patients from 9 unrelated families with LPI. Two of the mutations were large deletions involving exons 4 to 11 and exons 6 through 11 (603593.0011), respectively. These deletions were identified using multiplex ligation probe amplification (MLPA) assay and were found to result from the recombination of Alu repeats at introns 3 and 5, respectively, and the same AluY sequence in the 3-prime region of the SLC7A7 gene. Patients with the large deletions had the most severe phenotypes, likely resulting from dramatic loss of transport function.
In Finnish patients with lysinuric protein intolerance (LPI; 222700), Torrents et al. (1999) identified a homozygous A-to-T transversion in the acceptor splice site of intron 6 of the SLC7A7 gene. The mutation resulted in a 10-bp deletion beginning at nucleotide 1181, a frameshift, and premature protein truncation.
The same mutation was identified by Borsani et al. (1999) in 5 Finnish patients; they referred to the mutation as 1136-2A-T and found that it caused a 10-bp deletion due to the use of a second acceptor sequence, resulting in frameshift and premature termination 26 bp downstream.
Mykkanen et al. (2000) demonstrated that the Finnish founder mutant protein had no residual activity and remained intracellular.
Sperandeo et al. (2008) noted that this mutation corresponds to nucleotide 895-2A-T in the current nomenclature system.
In an Italian patient with lysinuric protein intolerance (LPI; 222700), born to consanguineous parents, Borsani et al. (1999) found homozygosity for a 543-bp deletion beginning at nucleotide 197 in the SLC7A7 gene.
Sperandeo et al. (2008) noted that this mutation corresponds to a 455-bp deletion spanning nucleotides 45 to 499 in exon 3 in the current nomenclature system.
In 4 Italian families, perhaps belonging to a single large pedigree, Borsani et al. (1999) found that members with lysinuric protein intolerance (LPI; 222700) were homozygous for a 4-bp insertion (1625insATCA) in exon 9 of the SLC7A7 gene, resulting in a frameshift at codon 462 and predicted translation termination 13 bp downstream.
Sperandeo et al. (2008) noted that this mutation corresponds to 1384insATCA in exon 10 of the SLC7A7 gene in the current nomenclature system.
In 2 brothers with lysinuric protein intolerance (LPI; 222700), Sperandeo et al. (2000) identified a homozygous 242A-C transversion in the SLC7A7 gene, resulting in a met1-to-leu (M1L) substitution. Sperandeo et al. (2000) stated that mutations of the translation-initiator ATG (MET1) are uncommon in inherited diseases.
Sperandeo et al. (2008) noted that this mutation corresponds to nucleotide 1A-C in exon 3 of the SLC7A7 gene in the current nomenclature system.
In a 15-year-old Spanish boy with clinical and laboratory findings compatible with lysinuric protein intolerance (LPI; 222700), Torrents et al. (1999) identified compound heterozygosity for 2 mutations in the SLC7A7 gene: a 1287T-G transversion resulting in a leu334-to-arg (L334R) substitution, and a 4-bp deletion (603593.0006). The missense mutation abolished y(+)LAT1 amino acid transport activity when coexpressed with 4F2hc in Xenopus laevis oocytes.
By functional expression studies, Mykkanen et al. (2000) found that the L334R mutant protein reached the oocyte plasma membrane when coexpressed with 4F2hc, but showed no transport activity.
Sperandeo et al. (2008) noted that this mutation corresponds to 1001T-G in exon 8 of the SLC7A7 gene in the current nomenclature system.
For discussion of the 4-bp deletion (1005delCTTT) in the SLC7A7 gene that was found in compound heterozygous state in a patient with lysinuric protein intolerance (LPI; 222700) by Torrents et al. (1999), see 603593.0005. The authors originally cited this mutation as 1291delCTTT.
Sperandeo et al. (2008) noted that this mutation corresponds to 1005delCTTT in exon 8 of the SLC7A7 gene in the current nomenclature system.
In 1 Latvian and 1 Estonian patient with lysinuric protein intolerance (LPI; 222700), Mykkanen et al. (2000) identified a homozygous 447G-T transversion in exon 3 of the SLC7A7 gene, resulting in a gly54-to-val (G54V) substitution in a highly conserved region. In vitro functional expression studies showed that the mutant G54V protein reached the oocyte plasma membrane when coexpressed with 4F2hc, but had no transport activity.
Sperandeo et al. (2008) noted that this mutation corresponds to 161G-T in exon 3 of the SLC7A7 gene in the current nomenclature system.
In affected members of 2 unrelated Japanese families with lysinuric protein intolerance (LPI; 222700), Noguchi et al. (2000) identified a homozygous 1514C-T transition in exon 9 of the SLC7A7 gene, resulting in an arg410-to-ter (R410X) substitution. In addition, 2 children from a third Japanese family were found to be compound heterozygous for R410X and another mutation (603593.0009).
Sperandeo et al. (2008) noted that this mutation corresponds to 1228C-T in exon 9 of the SLC7A7 gene in the current nomenclature system.
For discussion of the splice site mutation in the SLC7A7 gene that was found in compound heterozygous state in 2 children with lysinuric protein intolerance (LPI; 222700) by Noguchi et al. (2000), see 603593.0008. The authors cited this mutation as 911+1G-A.
Sperandeo et al. (2008) noted that this mutation corresponds to 625+1G-A in intron 4 of the SLC7A7 gene in the current nomenclature system and results in the skipping of exon 4.
In 2 unrelated patients with lysinuric protein intolerance (LPI; 222700), Sperandeo et al. (2000) identified a homozygous 967G-A transition in the SLC7A7 gene, resulting in a trp242-to-ter (W242X) substitution. Functional expression analysis has shown that the W242X mutant protein is retained in the Golgi and endoplasmic reticulum, is not expressed at the cell surface, and has no functional activity (Sperandeo et al., 2008).
Sperandeo et al. (2008) noted that this mutation corresponds to 726G-A in exon 5 of the SLC7A7 gene in the current nomenclature system.
In a Spanish patient with lysinuric protein intolerance (LPI; 222700), Font-Llitjos et al. (2009) identified a homozygous 4.6-kb deletion spanning intron 5 through exon 11 of the SLC7A7 gene. The deletion was identified using multiplex ligation probe amplification (MLPA) assay and was found to result from the recombination of Alu repeats in intron 5 and in the 3-prime region of the SLC7A7 gene. The patient had a severe phenotype with mental retardation.
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. SLC7A7, encoding a putative permease-related protein, is mutated in patients with lysinuric protein intolerance. Nature Genet. 21: 297-301, 1999. [PubMed: 10080183] [Full Text: https://doi.org/10.1038/6815]
Font-Llitjos, M., Rodriguez-Santiago, B., Espino, M., Sillue, R., Manas, S., Gomez, L., Perez-Jurado, L. A., Palacin, M., Nunes, V. Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat. Europ. J. Hum. Genet. 17: 71-79, 2009. [PubMed: 18716612] [Full Text: https://doi.org/10.1038/ejhg.2008.145]
Mykkanen, J., Torrents, D., Pineda, M., Camps, M., Yoldi, M. E., Horelli-Kuitunen, N., Huoponen, K., Heinonen, M., Oksanen, J., Simell, O., Savontaus, M.-L., Zorzano, A., Palacin, M., Aula, P. Functional analysis of novel mutations in y+LAT-1 amino acid transporter gene causing lysinuric protein intolerance (LPI). Hum. Molec. Genet. 9: 431-438, 2000. [PubMed: 10655553] [Full Text: https://doi.org/10.1093/hmg/9.3.431]
Noguchi, A., Shoji, Y., Koizumi, A., Takahashi, T., Shoji, Y., Matsumori, M., Kayo, T., Ohata, T., Wada, Y., Yoshimura, I., Maisawa, S., Konishi, M., Takasago, Y., Takada, G. SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families. Hum. Mutat. 15: 367-372, 2000. [PubMed: 10737982] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<367::AID-HUMU9>3.0.CO;2-C]
Puomila, K., Simell, O., Huoponen, K., Mykkanen, J. Two alternative promoters regulate the expression of lysinuric protein intolerance gene SLC7A7. Molec. Genet. Metab. 90: 298-306, 2007. [PubMed: 17196863] [Full Text: https://doi.org/10.1016/j.ymgme.2006.11.007]
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. Five novel SLC7A7 variants and y(+)L gene-expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance. Hum. Mutat. 20: 375-381, 2002. [PubMed: 12402335] [Full Text: https://doi.org/10.1002/humu.10140]
Sperandeo, M. P., Andria, G., Sebastio, G. Lysinuric protein intolerance: update and extended mutation analysis of the SLC7A7 gene. Hum. Mutat. 29: 14-21, 2008. [PubMed: 17764084] [Full Text: https://doi.org/10.1002/humu.20589]
Sperandeo, M. P., Bassi, M. T., Riboni, M., Parenti, G., Buoninconti, A., Manzoni, M., Incerti, B., Larocca, M. R., Di Rocco, M., Strisciuglio, P., Dianzani, I., Parini, R., Candito, M., Endo, F., Ballabio, A., Andria, G., Sebastio, G., Borsani, G. Structure of the SLC7A7 gene and mutational analysis of patients affected by lysinuric protein intolerance. Am. J. Hum. Genet. 66: 92-99, 2000. [PubMed: 10631139] [Full Text: https://doi.org/10.1086/302700]
Torrents, D., Estevez, R., Pineda, M., Fernandez, E., Lloberas, J., Shi, Y.-B., Zorzano, A., Palacin, M. Identification and characterization of a membrane protein ((+)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. J. Biol. Chem. 273: 32437-32445, 1998. [PubMed: 9829974] [Full Text: https://doi.org/10.1074/jbc.273.49.32437]
Torrents, D., Mykkanen, J., Pineda, M., Feliubadalo, L., Estevez, R., de Cid, R., Sanjurjo, P., Zorzano, A., Nunes, V., Huoponen, K., Reinikainen, A., Simell, O., Savontaus, M.-L., Aula, P., Palacin, M. Identification of SLC7A7, encoding y(+)LAT-1, as the lysinuric protein intolerance gene. Nature Genet. 21: 293-296, 1999. [PubMed: 10080182] [Full Text: https://doi.org/10.1038/6809]