Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Target Concepts:
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Query: UMLS:C0018991 (
hemiplegia
)
3,997
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
SLC1A3 encodes the glial glutamate transporter hEAAT1, which removes glutamate from the synaptic cleft via stoichiometrically coupled Na
+
-K
+
-H
+
-glutamate transport. In a young man with migraine with aura including
hemiplegia
, we identified a novel SLC1A3 mutation that predicts the substitution of a conserved threonine by
proline
at position 387 (T387P) in hEAAT1. To evaluate the functional effects of the novel variant, we expressed the wildtype or mutant hEAAT1 in mammalian cells and performed whole-cell patch clamp, fast substrate application, and biochemical analyses. T387P diminishes hEAAT1 glutamate uptake rates and reduces the number of hEAAT1 in the surface membrane. Whereas hEAAT1 anion currents display normal ligand and voltage dependence in cells internally dialyzed with Na
+
-based solution, no anion currents were observed with internal K
+
. Fast substrate application demonstrated that T387P abolishes K
+
-bound retranslocation. Our finding expands the phenotypic spectrum of genetic variation in SLC1A3 and highlights impaired K
+
binding to hEAAT1 as a novel mechanism of glutamate transport dysfunction in human disease.
...
PMID:Impaired K
+
binding to glial glutamate transporter EAAT1 in migraine. 2906 57
Episodic ataxia type 6 is an inherited neurological condition characterized by combined ataxia and epilepsy. A severe form of this disease with episodes combining ataxia, epilepsy and
hemiplegia
was recently associated with a
proline
to arginine substitution at position 290 of the excitatory amino acid transporter 1 in a heterozygous patient. The excitatory amino acid transporter 1 is the predominant glial glutamate transporter in the cerebellum. However, this glutamate transporter also functions as an anion channel and earlier work in heterologous expression systems demonstrated that the mutation impairs the glutamate transport rate, while increasing channel activity. To understand how these changes cause ataxia, we developed a constitutive transgenic mouse model. Transgenic mice display epilepsy, ataxia and cerebellar atrophy and, thus, closely resemble the human disease. We observed increased glutamate-activated chloride efflux in Bergmann glia that triggers the apoptosis of these cells during infancy. The loss of Bergmann glia results in reduced glutamate uptake and impaired neural network formation in the cerebellar cortex. This study shows how gain-of-function of glutamate transporter-associated anion channels causes ataxia through modifying cerebellar development.
...
PMID:Increased glutamate transporter-associated anion currents cause glial apoptosis in episodic ataxia 6. 3295 83
