Alternative titles; symbols
HGNC Approved Gene Symbol: SLC1A4
SNOMEDCT: 1237418002;
Cytogenetic location: 2p14 Genomic coordinates (GRCh38): 2:64,988,479-65,023,865 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p14 | Spastic tetraplegia, thin corpus callosum, and progressive microcephaly | 616657 | Autosomal recessive | 3 |
The SLC1A4 gene encodes the Na(+)-dependent neutral amino acid transporter ASCT1, which transports L-serine, L-alanine, L-cysteine, and L-threonine. In the brain, L-serine is synthesized by astrocytes and is shuttled into neuronal cells by the dedicated SLC1A4 transporter; L-serine is considered an essential amino acid for neurons (summary by Heimer et al., 2015 and Damseh et al., 2015).
In a screening for cDNAs encoding proteins similar to the sodium-coupled glutamate transporter GLAST1 (SLC1A3; 600111), Hofmann et al. (1994) isolated a cDNA clone encoding a protein that was identical to the neutral amino acid transporter ASCT1 (Arriza et al., 1993; Shafqat et al., 1993). The open reading frame of 1,572 basepairs encodes a deduced 524-amino acid protein.
Hofmann et al. (1994) determined that the SLC1A4 gene contains 8 exons spanning at least 40 kb of genomic DNA.
Hofmann et al. (1994) mapped the SLC1A4 gene to 2p15-p13 by fluorescence in situ hybridization.
Hartz (2011) mapped the SLC1A4 gene to chromosome 2p14 based on an alignment of the SLC1A4 sequence (GenBank AB026689) with the genomic sequence (GRCh37).
ASCT1 does not transport glutamate or aspartate but alanine, serine, cysteine, and threonine instead (Hofmann et al., 1994).
Zerangue and Kavanaugh (1996) found that the ASCT1 transporter functions primarily as an amino acid exchanger. Transport is associated with a chloride channel activity that is thermodynamically uncoupled from amino acid transport.
In 2 sibs, born of consanguineous Ashkenazi Jewish parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Srour et al. (2015) identified a homozygous missense mutation in the SLC1A4 gene (E256K; 600229.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Srour et al. (2015) proposed that disruption of SLC1A4 impairs brain development and function by decreasing the availability of L-serine in neurons.
Heimer et al. (2015) identified a homozygous E256K mutation in the SLC1A4 gene in a 4.5-year-old girl of Ashkenazi Jewish descent with SPATCCM. An unrelated girl of Ashkenazi-Iraqi descent with the disorder was compound heterozygous for E256K and a truncating mutation (600229.0002). Functional studies of the variants were not performed.
Damseh et al. (2015) identified a homozygous E256K mutation in the SLC1A4 gene in 9 patients from 7 unrelated families of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Haplotype analysis indicated that the E256K mutation was a founder mutation in the Ashkenazi Jewish population. In vitro functional expression studies in HEK cells showed that L-serine and L-alanine transport by the E256K variant was reduced by 25% and 20%, respectively, compared to wildtype. Another patient, born of an Ashkenazi Jewish father and an Iraqi-Jewish mother, was compound heterozygous for the E256K mutation and a frameshift mutation (600229.0002). A different homozygous missense mutation in the SLC1A4 gene (R457W; 600229.0003) was found in a girl, born of consanguineous Palestinian parents, with SPATCCM. In vitro functional expression studies in HEK cells showed no measurable substrate transport activity for the R457W variant.
In a boy, born to third-cousin parents of Irish descent, with SPATCCM, Conroy et al. (2016) identified a homozygous nonsense mutation in the SLC1A4 gene (W453X; 600229.0004). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The authors noted that this was the first patient of European background to be identified with this disorder and that investigation for SLC1A4 mutations should be undertaken regardless of ethnicity.
In a 7-year-old boy, born to parents from the same small city in southern Italy, with SPATCCM, Pironti et al. (2018) identified a homozygous missense mutation in the SLC1A4 gene (G381R; 600229.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
In 2 sibs, born of consanguineous Ashkenazi Jewish parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Srour et al. (2015) identified a homozygous c.766G-A transition (rs201278558) in the SLC1A4 gene, resulting in a glu256-to-lys (E256K) substitution at a highly conserved residue in the middle of the protein at the junction between its second intracellular loop and transmembrane domain 5. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Variant Server databases and 700 in-house exomes. The mutation segregated with the disorder in the family. The reported frequency in control databases was very low: 0.000077 in the Exome Variant Server, and 0.00017 in the ExAC database. It was found in heterozygous state in 5 of 540 Ashkenazi Jewish control individuals (allele frequency of 0.0056). Functional studies of the variant were not performed.
Heimer et al. (2015) identified a homozygous E256K mutation in the SLC1A4 gene in a 4.5-year-old girl of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated girl of Ashkenazi-Iraqi descent with the disorder was compound heterozygous for E256K and a 2-bp deletion (600229.0002), which the authors cited as c.945delTT, resulting in a frameshift and premature termination (Leu315HisfsTer42). The E256K mutation was found in 1 of 100 Ashkenazi Jewish controls, but was either absent or at very low frequency in other general population databases. Functional studies of the variants were not performed.
Damseh et al. (2015) identified a homozygous E256K mutation in 9 patients from 7 unrelated families of Ashkenazi Jewish descent with SPATCCM. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Among 860 control individuals of Ashkenazi Jewish descent, 6 carried the variant (frequency of carriers in this population estimated to be 0.7%). The variant was also found in 21 of over 60,000 individuals in the ExAC database. Haplotype analysis indicated that the E256K mutation was a founder mutation in the Ashkenazi Jewish population. In vitro functional expression studies in HEK cells showed that L-serine and L-alanine transport by the E256K variant was reduced by 25% and 20%, respectively, compared to wildtype. Another patient, born of an Ashkenazi Jewish father and an Iraqi-Jewish mother, was compound heterozygous for the E256K mutation and a 2-bp deletion, c.944_945del (600229.0002), resulting in a frameshift and premature termination (Leu315fs).
For discussion of the c.944_945delTT mutation (c.944_945delTT, NM_003038.4) in the SLC1A4 gene, resulting in a frameshift and premature termination (Leu315HisfsTer42) that was found in compound heterozygous state in patients with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657) by Heimer et al. (2015) and Damseh et al. (2015), see 600229.0001.
In a girl, born of consanguineous Palestinian parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Damseh et al. (2015) identified a homozygous c.1369C-T transition (c.1369C-T, NM_003038) in the SLC1A4 gene, resulting in an arg457-to-trp (R457W) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in 19 of over 60,000 individuals in the ExAC database; no homozygotes were present in that cohort. In vitro functional expression studies in HEK cells showed no measurable substrate transport activity for the R457W variant.
In a boy, born to third-cousin parents of Irish descent, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Conroy et al. (2016) identified a homozygous c.1358G-A transition in the SLC1A4 gene, resulting in a trp453-to-ter (W453X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. In homozygous state, the protein was missing the final 80 amino acids, presumably leading to a loss-of-function effect. The variant was not present in the EVS or ExAC databases or in an in-house Irish control database of 97 individuals. Conroy et al. (2016) noted that this was the first patient of European background to be identified with this disorder.
In a 7-year-old boy, born to parents who came from the same small city in southern Italy, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Pironti et al. (2018) identified a homozygous c.1141G-A transition (c.1141G-A, NM_003038.4) in the SLC1A4 gene, resulting in a gly381-to-arg (G381R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The variant was not found in the 1000 Genomes Project or ExAC databases or in an in-house database containing over 6,000 individuals.
Arriza, J. L., Kavanaugh, M. P., Fairman, W. A., Wu, Y.-N., Murdoch, G. H., North, R. A., Amara, S. G. Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J. Biol. Chem. 268: 15329-15332, 1993. [PubMed: 8101838]
Conroy, J., Allen, N. M., Gorman, K., O'Halloran, E., Shahwan, A., Lynch, B., Lynch, S. A., Ennis, S., King, M. D. Novel European SLC1A4 variant: infantile spasms and population ancestry analysis. J. Hum. Genet. 61: 761-764, 2016. [PubMed: 27193218] [Full Text: https://doi.org/10.1038/jhg.2016.44]
Damseh, N., Simonin, A., Jalas, C., Picoraro, J. A., Shaag, A., Cho, M. T., Yaacov, B., Neidich, J., Al-Ashhab, M., Juusola, J., Bale, S., Telegrafi, A., and 10 others. Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. J. Med. Genet. 52: 541-547, 2015. [PubMed: 26041762] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103104]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/1/2011.
Heimer, G., Marek-Yagel, D., Eyal, E., Barel, O., Oz Levi, D., Hoffmann, C., Ruzzo, E. K., Ganelin-Cohen, E., Lancet, D., Pras, E., Rechavi, G., Nissenkorn, A., Anikster, Y., Goldstein, D. B., Ben Zeev, B. SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum. Clin. Genet. 88: 327-335, 2015. [PubMed: 26138499] [Full Text: https://doi.org/10.1111/cge.12637]
Hofmann, K., Duker, M., Fink, T., Lichter, P., Stoffel, W. Human neutral amino acid transporter ASCT1: structure of the gene (SLC1A4) and localization to chromosome 2p13-p15. Genomics 24: 20-26, 1994. [PubMed: 7896285] [Full Text: https://doi.org/10.1006/geno.1994.1577]
Pironti, E., Salpietro, V., Cucinotta, F., Granata, F., Mormina, E., Efthymiou, S., Scuderi, C., Gagliano, A., Houlden, H., Di Rosa, G. A novel SLC1A4 homozygous mutation causing congenital microcephaly, epileptic encephalopathy and spastic tetraparesis: a video-EEG and tractography--case study. J. Neurogenet. 32: 316-321, 2018. [PubMed: 29989513] [Full Text: https://doi.org/10.1080/01677063.2018.1476510]
Shafqat, S., Tamarappoo, B. K., Kilberg, M. S., Puranam, R. S., McNamara, J. O., Guadano-Ferraz, A., Fremeau, R. T., Jr. Cloning and expression of a novel Na(+)-dependent neutral amino acid transporter structurally related to mammalian Na(+)/glutamate cotransporters. J. Biol. Chem. 268: 15351-15355, 1993. [PubMed: 8340364]
Srour, M., Hamdan, F. F., Gan-Or, Z., Labuda, D., Nassif, C., Oskoui, M., Gana-Weisz, M., Orr-Urtreger, A., Rouleau, G. A., Michaud, J. L. A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly. Clin. Genet. 88: e1-e4, 2015. Note: Electronic Article. [PubMed: 25930971] [Full Text: https://doi.org/10.1111/cge.12605]
Zerangue, N., Kavanaugh, M. P. ASCT-1 is a neutral amino acid exchanger with chloride channel activity. J. Biol. Chem. 271: 27991-27994, 1996. [PubMed: 8910405] [Full Text: https://doi.org/10.1074/jbc.271.45.27991]