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Table of Contents for *604159
Title
Gene-Phenotype Relationships
Text
Description
Cloning and Expression
Mapping
Molecular Genetics
Animal Model
Allelic Variants
Table View
References
Contributors
Creation Date
Edit History
*604159
SOLUTE CARRIER FAMILY 6 (NEUROTRANSMITTER TRANSPORTER, GLYCINE), MEMBER 5; SLC6A5

Alternative titles; symbols
GLYCINE TRANSPORTER, TYPE 2; GLYT2

HGNC Approved Gene Symbol: SLC6A5

Cytogenetic location: 11p15.1     Genomic coordinates (GRCh37): 11:20,620,945-20,676,609 (from NCBI)

Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number		 Inheritance
(in progress)		 Phenotype
mapping key
11p15.1 Hyperekplexia 3 614618 AR, AD 3

TEXT
Description
The SLC6A5 gene encodes a presynaptic glycine transporter. The amino acid glycine is a major inhibitory neurotransmitter in the spinal cord, brainstem, and retina, where it exerts its effects on the strychnine-sensitive glycine receptors. In addition, glycine acts as a coagonist with glutamate at the N-methyl-D-aspartate (NMDA) receptors (see 138252). The termination of action of glycine, like that of most other neurotransmitters, is mediated by rapid reuptake into the presynaptic terminal or surrounding glial cells. Glycine transporters are members of the sodium/chloride-dependent transporter family, which share 40 to 50% amino acid similarity and are characterized by 12 putative transmembrane regions (summary by Liu et al., 1993).

Cloning and Expression
Liu et al. (1993) isolated a rat brain cDNA encoding a novel glycine transporter, which they called GlyT2. They found that GlyT2 differs from GlyT1 (601019) in molecular structure, tissue specificity, and pharmacologic properties. By PCR of a human brain cDNA library with primers based on conserved regions of the rat GlyT2 gene, Morrow et al. (1998) cloned a cDNA corresponding to human GLYT2. The predicted 797-amino acid human protein is 94% identical to rat GlyT2. When expressed in mammalian cells, GLYT2 displayed high affinity glycine uptake. Northern blot analysis of central nervous system tissues revealed that the approximately 9.5-kb GLYT2 mRNA is expressed in medulla, and to a lesser extent in spinal cord and cerebellum. Morrow et al. (1998) stated that the previously characterized GLYT1 and GLYT2 localization patterns suggest that GLYT2 is responsible for the termination of neurotransmission at strychnine-sensitive glycinergic synapses, while the more widely expressed GLYT1 may play a role in regulation of glycine levels in NMDA receptor-mediated neurotransmission. Independently, Gallagher et al. (1999) isolated cDNAs encoding 3 isoforms of GLYT2.

Mapping
By analysis of a radiation hybrid panel, Morrow et al. (1998) mapped the GLYT2 gene to chromosome 11p15.2-p15.1.

Molecular Genetics
In 6 patients, including 2 brothers, with hyperekplexia-3 (HKPX3; 614618), Rees et al. (2006) identified homozygous or compound heterozygous mutations in the SLC6A5 gene (see, e.g., 604159.0001-604159.0007). An additional patient with the disorder was found to carry a heterozygous mutation (604159.0008), consistent with autosomal dominant inheritance. Individuals with mutations in SLC6A5 presented with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. In vitro functional expression studies demonstrated that the SLC6A5 mutations resulted in defective subcellular localization of glycine transporter-2, decreased lysine uptake, or both, with selected mutations affecting predicted glycine and Na+ binding sites.

Rees et al. (2006) stated that the SLC6A5-related form of hyperekplexia was the first neurologic disorder linked to alterations in a Na(+)/Cl(-)-dependent transporter for a classic fast neurotransmitter. They suggested that in other human disorders where defects in postsynaptic receptors have been identified, similar symptoms could result from defects in the cognate presynaptic neurotransmitter transporter. In the hierarchical genetic analysis of hyperekplexia, SLC6A5 must be regarded as an important candidate gene and have equal priority to GLRA1 (138491) in screening. GLYT2 accessory proteins such as syntenin (602217) and ULIP6 (608383) that are involved in the correct localization of GLYT2 at presynaptic terminals must also be considered as candidates in individuals with hyperekplexia awaiting definitive genetic diagnosis. Mutations in SLC6A5 should be regarded as a risk factor for sudden infant death syndrome (272120).

Animal Model
Rees et al. (2006) noted that although mouse knockouts of GlyT2 have been suggested to show behavioral phenotypes similar to human hyperekplexia (Gomeza et al., 2003), there are several marked differences from individuals with mutations in the human gene. GlyT2 knockout mice gain weight slowly and die prematurely at the end of the second postnatal week, showing a complex neurologic phenotype characterized by spasticity, a severely impaired righting reflex and, of particular note, rigid muscle tone and strong spontaneous tremor. By contrast, humans with mutations in SLC6A5 show no spontaneous tremor or muscle stiffness, although these can be triggered by acoustic or tactile stimuli.

ALLELIC VARIANTS (8 Selected Examples):

   Table View          ClinVar   

.0001 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, TYR377TER [dbSNP:rs121908493] [ClinVar]
In a Canadian patient with hyperekplexia-3 (HKPX3; 614618), Rees et al. (2006) found compound heterozygosity for 2 mutations in the SLC6A5 gene: a 1131C-A transversion in exon 7 resulting in an in-frame stop codon (tyr377-to-stop, Y377X) and protein truncation in the paternal allele; and in the maternal allele, a 1294G-T transversion and insertion of a T after nucleotide 1295, resulting in a val432-to-phe (V432F) substitution and frameshift with protein truncation (604159.0002). The patient was severely affected. While the mother exhibited a partial hyperekplectic phenotype, the Y377X paternal allele did not evoke a hyperekplectic phenotype in the father.

.0002 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, VAL432PHE [dbSNP:rs281864924] [ClinVar]
For discussion of the val432-to-phe (V432F) mutation in the SLC6A5 gene that was found in compound heterozygous state in a patient with hyperekplexia-3 (HKPX3; 614618) by Rees et al. (2006), see 604159.0001.

.0003 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, TYR491CYS [dbSNP:rs121908494] [ClinVar]
In a patient with hyperekplexia-3 (HKPX3; 614618) from the United States, Rees et al. (2006) found compound heterozygosity for a missense and a nonsense mutation in the SLC6A5 gene: a 1472A-G transition in exon 9 resulting in a tyr491-to-cys substitution (Y491C), and a 1888C-T transition in exon 13 resulting in a gln630-to-stop substitution (Q630X; 604159.0004). The parents were unaffected but declined participation in molecular studies.

.0004 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, GLN630TER [dbSNP:rs121908495] [ClinVar]
For discussion of the gln630-to-ter (Q630X) mutation in the SLC6A5 gene that was found in compound heterozygous state in a patient with hyperekplexia-3 (HKPX3; 614618) by Rees et al. (2006), see 604159.0003.

.0005 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, LEU306VAL [dbSNP:rs121908496] [ClinVar]
In a patient in the Netherlands with hyperekplexia-3 (HKPX3; 614618), Rees et al. (2006) found compound heterozygosity for 2 missense mutations in the SLC6A5 gene: a 916C-G transversion in exon 5 resulting in a leu306-to-val substitution (L306V) and a 1526A-G transition in exon 10 resulting in an asn509-to-ser substitution (N509S; 604159.0006), on the paternal and maternal alleles, respectively.

.0006 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, ASN509SER [dbSNP:rs121908497] [ClinVar]
For discussion of the asn509-to-ser (N509S) mutation in the SLC6A5 gene that was found in compound heterozygous state in a patient with hyperekplexia-3 (HKPX3; 614618) by Rees et al. (2006), see 604159.0005.

.0007 HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE
SLC6A5, THR425MET [dbSNP:rs121908498] [ClinVar]
In a patient in the Netherlands with hyperekplexia-3 (HKPX3; 614618), Rees et al. (2006) found homozygosity for a missense mutation in the SLC6A5 gene, thr425-to-met (T425M), inherited from consanguineous parents. The mutation arose from a 1274C-T transition in exon 8.

.0008 HYPEREKPLEXIA 3, AUTOSOMAL DOMINANT
SLC6A5, SER510ARG [dbSNP:rs281864926] [ClinVar]
In a patient with hyperekplexia-3 (HKPX3; 614618), Rees et al. (2006) identified a heterozygous 1530T-G transversion in exon 10 of the SLC6A65 gene, resulting in a ser510-to-arg (S510R) substitution on the maternal allele. The paternal allele carried an ala89-to-glu (A89E) polymorphism that was detected in 4 of 203 controls. In vitro functional expression studies showed that S510R formed intracellular aggregates, abolished glycine uptake, and caused a dominant-negative effect.

REFERENCES
1. Gallagher, M. J., Burgess, L. H., Brunden, K. R. Characterization of multiple forms of the human glycine transporter type-2. Molec. Brain Res. 70: 101-115, 1999. [PubMed: 10381548, related citations] [Full Text]

2. Gomeza, J., Ohno, K., Hulsmann, S., Armsen, W., Eulenburg, V., Richter, D. W., Laube, B., Betz, H. Deletion of the mouse glycine transporter 2 results in a hyperekplexia phenotype and postnatal lethality. Neuron 40: 797-806, 2003. [PubMed: 14622583, related citations] [Full Text]

3. Liu, Q. R., Lopez-Corcuera, B., Mandiyan, S., Nelson, H., Nelson, N. Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features. J. Biol. Chem. 268: 22802-22808, 1993. [PubMed: 8226790, related citations] [Full Text]

4. Morrow, J. A., Collie, I. T., Dunbar, D. R., Walker, G. B., Shahid, M., Hill, D. R. Molecular cloning and functional expression of the human glycine transporter GlyT2 and chromosomal localisation of the gene in the human genome. FEBS Lett. 439: 334-340, 1998. [PubMed: 9845349, related citations] [Full Text]

5. Rees, M. I., Harvey, K., Pearce, B. R., Chung, S.-K., Duguid, I. C., Thomas, P., Beatty, S., Graham, G. E., Armstrong, L., Shiang, R., Abbott, K. J., Zuberi, S. M., Stephenson, J. B. P., Owen, M. J., Tijssen, M. A. J., van den Maagdenberg, A. M. J. M., Smart, T. G., Supplisson, S., Harvey, R. J. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nature Genet. 38: 801-806, 2006. [PubMed: 16751771, images, related citations] [Full Text]


▸ Contributors: Cassandra L. Kniffin - updated : 5/8/2012
Creation Date: Rebekah S. Rasooly : 9/5/1999
▸ Edit History: mcolton : 07/23/2015



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