Alternative titles; symbols
HGNC Approved Gene Symbol: SLC32A1
Cytogenetic location: 20q11.23 Genomic coordinates (GRCh38) : 20:38,724,486-38,729,372 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.23 | Developmental and epileptic encephalopathy 114 | 620774 | Autosomal dominant | 3 |
| Generalized epilepsy with febrile seizures plus, type 12 | 620755 | Autosomal dominant | 3 |
Gamma-aminobutyric acid (GABA) is a major inhibitory transmitter. SLC32A1 is an amino acid transporter that loads GABA and glycine into synaptic vesicles (summary by Jellali et al., 2002).
McIntire et al. (1997) identified Slc32a1, or Unc47, as a vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) in C. elegans. C. elegans Unc47 contains 486 amino acids and has 10 transmembrane domains. Fluorescence-tagged Unc47 was expressed only in GABAergic neurons of C. elegans and localized to synaptic vesicles along the ventral and dorsal cords. The authors also cloned the rat Unc47 ortholog, which encodes a 525-amino acid protein 38% identical to C. elegans Unc47. Rat Unc47 contains 10 predicted transmembrane domains, with both N and C termini residing in the cytoplasm. The N-terminal domain is hydrophilic and large (132 residues). Northern blot analysis detected a 2.5-kb Unc47 transcript in rat brain, with not in nonneural tissues. However, RT-PCR analysis detected Unc47 expression in rat spleen, testis, and pancreas, in addition to brain. In situ hybridization of rat brain demonstrated Unc47 expression in regions containing abundant GABAergic neurons. Immunofluorescence analysis localized Unc47 to intracellular membrane vesicles in transfected rat pheochromocytoma PC12 cells.
By confocal immunohistochemical analysis of mouse retina, Jellali et al. (2002) found that Slc32a1, which they called Viaat, was expressed in inner and outer plexiform layers. In the outer plexiform layer, Viaat was detected in horizontal cells, where it localized to punctate structures at cell tips in close apposition to rod and cone photoreceptor cell terminals and rod bipolar cell dendrites. In human retina, VIAAT staining was predominantly observed in the inner plexiform layer. In cultured adult human retinal cells, VIAAT was expressed in horizontal cells, either at their terminals or throughout the cell body.
Hartz (2015) mapped the SLC32A1 gene to chromosome 20q11.23 based on an alignment of the SLC32A1 sequence (GenBank AK055051) with the genomic sequence (GRCh38).
McIntire et al. (1997) found that rat Unc47 conferred vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those reported for synaptic vesicles from brain.
In mice, Oka et al. (2015) identified 2 distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. The authors showed that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV1 (600541), evokes intense drinking behavior, even in fully water-satiated animals. The light-induced response, which is highly specific for water, is both immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. Oka et al. (2015) concluded that these results revealed an innate brain circuit that can turn an animal's water-drinking behavior on and off and that probably functions as a center for thirst control in the mammalian brain.
Generalized Epilepsy with Febrile Seizures Plus, Type 12
In affected members of 6 unrelated families with type 12 generalized epilepsy with febrile seizures plus (GEFSP12; 620755), Heron et al. (2021) identified heterozygous missense mutations in the SLC32A1 gene (see, e.g., 616440.0001-616440.0004). The mutations, which were found by whole-genome or exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Incomplete penetrance was observed in 1 family (family B). None of the variants was present in the gnomAD database. The mutations occurred throughout the gene, with several clustering in the eighth transmembrane domain. Functional studies of the variants and studies of patient cells were not performed, but in silico analysis suggested that they could alter GABAergic signaling, leading to increased seizure susceptibility. The authors postulated a partial loss-of-function effect with reduced neuronal inhibition. Two additional families (families G and H) with a similar phenotype and heterozygous SLC32A1 variants were identified, although the evidence for pathogenicity in these families was conflicting.
Developmental and Epileptic Encephalopathy 114
In 4 unrelated patients with developmental and epileptic encephalopathy-114 (DEE114; 620774), Platzer et al. (2022) identified de novo heterozygous missense mutations in the SLC32A1 gene: V263M (616440.0005), L269P (616440.0006), F322C (616440.0007), and A91T. The mutations were identified by whole-exome sequencing. Murine Slc32a1 with each corresponding mutation was expressed in mouse striatal GABAergic Slc32a1-knockout neurons in culture. The V263M, L269P, and F322C variants, which occurred at conserved residues, resulted in reduced inhibitory postsynaptic currents and reduced quantal size compared to wildtype. The mouse A90T mutation corresponding to the human A91T variant resulted in elevated vesicular release probability. When these mutations were expressed in GABAergic mouse neurons that had either wildtype or heterozygosity for a knockout mutation in Slc32a1, no synaptic abnormalities were identified, indicating that the mutations did not have a dominant-negative effect. The authors noted that the A91T variant occurred at a nonconserved residue and was identified in a patient (patient 1) who was also found to have a de novo heterozygous missense mutation in the CACNA1H gene (607904), which the authors considered noncausative.
In 8 affected members of a 3-generation family of English ancestry (family A, previously reported as family AA by Zhang et al. (2017)) with type 12 generalized epilepsy with febrile seizures plus (GEFSP12; 620755), Heron et al. (2021) identified a heterozygous c.1403T-C transition (c.1403T-C, NM_080552.3) in the SLC32A1 gene, predicted to result in a leu468-to-pro (L468P) substitution at a conserved residue in the eighth transmembrane domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but in silico analysis suggested that the variant could alter GABAergic signaling, leading to increased seizure susceptibility.
In 8 affected individuals spanning 2 generations of a family of English ancestry (family B) with type 12 generalized epilepsy with febrile seizures plus (GEFSP12; 620755), Heron et al. (2021) identified a heterozygous c.989T-C transition (c.989T-C, NM_080552.3) in the SLC32A1 gene, resulting in a met330-to-thr (M330T) substitution at a conserved residue in one of the cytosolic loops. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two unaffected family members also carried the mutation, indicating incomplete penetrance. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but in silico analysis suggested that the variant could alter GABAergic signaling, leading to increased seizure susceptibility.
In 3 individuals spanning 3 generations of a family (family C) with type 12 generalized epilepsy with febrile seizures plus (GEFSP12; 620755), Heron et al. (2021) identified a heterozygous c.1391C-G transversion (c.1391C-G, NM_080552.3) in the SLC32A1 gene, resulting in a thr464-to-arg (T464R) substitution at a conserved residue in the eighth transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but in silico analysis suggested that the variant could alter GABAergic signaling, leading to increased seizure susceptibility.
In 2 sibs (family E) with type 12 generalized epilepsy with febrile seizures plus (GEFSP12; 620755), Heron et al. (2021) identified a heterozygous c.1382G-A transition (c.1382G-A, NM_080552.3) in the SLC32A1 gene, resulting in a gly461-to-asp (G461D) substitution at a conserved residue in the eighth transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but in silico analysis suggested that the variant could alter GABAergic signaling, leading to increased seizure susceptibility.
In a patient (patient 2) with developmental and epileptic encephalopathy-114 (DEE114; 620774), Platzer et al. (2022) identified a de novo heterozygous c.787G-A transition (c.787G-A, NM_080552.3) in the SLC32A1 gene, resulting in a val263-to-met (V263M) substitution at a highly conserved residue. The mutation, which was identified by trio whole-exome sequencing, was not present in the gnomAD database (v2.1.1). Structural modeling demonstrated that the V263M mutation was located in a transmembrane domain and may affect substrate uptake.
In a patient (patient 3) with developmental and epileptic encephalopathy-114 (DEE114; 620774), Platzer et al. (2022) identified a de novo heterozygous c.806T-C transition (c.806T-C, NM_080552.3) in the SLC32A1 gene, resulting in a leu269-to-pro (L269P) substitution at a highly conserved residue. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). Structural modeling demonstrated that the L269P mutation was located in a transmembrane domain and may affect substrate uptake.
In a patient (patient 4) with developmental and epileptic encephalopathy-114 (DEE114; 620774), Platzer et al. (2022) identified a de novo heterozygous c.965T-G transversion (c.965T-G, NM_080552.3) in the SLC32A1 gene, resulting in a phe322-to-cys (F322C) substitution at a highly conserved residue. The mutation, which was identified by exome sequencing of the SLC32A1 gene and confirmed by Sanger sequencing, was not present in the gnomAD database (v2.1.1). Structural modeling demonstrated that the F322C mutation was located in a transmembrane domain and may affect substrate uptake.
Hartz, P. A. Personal Communication. Baltimore, Md. 6/25/2015.
Heron, S. E., Regan, B. M., Harris, R. V., Gardner, A. E., Coleman, M. J., Bennett, M. F., Grinton, B. E., Helbig, K. L., Sperling, M. R., Haut, S., Geller, E. B., Widdess-Walsh, P., and 9 others. Association of SLC32A1 missense variants with genetic epilepsy with febrile seizures plus. Neurology 96: e2251-e2260, 2021. [PubMed: 34038384] [Full Text: https://doi.org/10.1212/WNL.0000000000011855]
Jellali, A., Stussi-Garaud, C., Gasnier, B., Rendon, A., Sahel, J.-A., Dreyfus, H., Picaud, S. Cellular localization of the vesicular inhibitory amino acid transporter in the mouse and human retina. J. Comp. Neurol. 449: 76-87, 2002. [PubMed: 12115694] [Full Text: https://doi.org/10.1002/cne.10272]
McIntire, S. L., Reimer, R. J., Schuske, K., Edwards, R. H., Jorgensen, E. M. Identification and characterization of the vesicular GABA transporter. Nature 389: 870-876, 1997. [PubMed: 9349821] [Full Text: https://doi.org/10.1038/39908]
Oka, Y., Ye, M., Zuker, C. S. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature 520: 349-352, 2015. [PubMed: 25624099] [Full Text: https://doi.org/10.1038/nature14108]
Platzer, K., Sticht, H., Bupp, C., Ganapathi, M., Pereira, E. M., Le Guyader, G., Bilan, F., Henderson, L. B., Lemke, J. R., Taschenberger, H., Brose, N., Abou Jamra, R., Wojcik, S. M. De novo missense variants in SLC32A1 cause a developmental and epileptic encephalopathy due to impaired GABAergic neurotransmission. Ann. Neurol. 92: 958-973, 2022. [PubMed: 36073542] [Full Text: https://doi.org/10.1002/ana.26485]
Zhang, Y.-H., Burgess, R., Malone, J. P., Glubb, G. C., Helbig, K. L., Vadlamudi, L., Kivity, S., Afawi, Z., Bleasel, A., Grattan-Smith, P., Grinton, B. E., Bellows, S. T., and 9 others. Genetic epilepsy with febrile seizures plus: refining the spectrum. Neurology 89: 1210-1219, 2017. [PubMed: 28842445] [Full Text: https://doi.org/10.1212/WNL.0000000000004384]