Titel: SLC1A2 is a new candidate gene for neuromyelitis optica spectrum disorder
ID: P-Compl-120
Art: Postertalk
Redezeit: 2 min
Session: Poster Session
Compl / Techno / Therap

Referent: Michelle Meyenborg (Kiel/DE)

Abstract - Text


Atypical inflammatory demyelinating (AID) syndromes are a heterogeneous group of rare inflammatory diseases of the central nervous system. In contrast to multiple sclerosis they do not present the characteristic MRI findings or clinical symptoms. They also show a poor response to treatments that are used against multiple sclerosis. The clinical course of disease in patients with AID syndromes is heterogeneous. Some patients recover completely whereas other patients have quick disease progress with poor prognosis. One of these syndromes is neuromyelitis optica spectrum disorder (NMOSD). Patients present multiple motor and cognitive disorders with different expression. In most patients with NMOSD, IgG autoantibodies against aquaporin-4 (AQP4), a water channel localized in astrocytes, were found.

A 37 years old male presented with neurological symptoms e.g. optic neuritis, spastic tetraparesis and hyperreflexia. Serological tests for AQP4 autoantibodies gave negative results. After other potential diseases had been excluded, the patient's symptoms led to the suspicion of NMOSD. But even though different immunomodulatory therapies were escalated, the disease progressed rapidly. Using exome sequencing, we identified the heterozygous variant c.343C>T [p(Arg115CysSLC)] in SLC1A2. SLC1A2 is a protein coding gene which encodes a sodium dependent amino acid transporter. It is localized on the presynaptic membrane on astrocytes and removes L-glutamate, L-aspartate and D-aspartate from the synaptic cleft. According to prediction tools (e.g. REVEL, CADD, SIFT, PROVEAN), the amino acid exchange from arginine to cysteine at position 115 is predicted to be pathogenic or protein damaging. The affected arginine residue is located in the sodiumdicarboxylate symporter family-domain, is highly preserved and is involved in ligand-interactions. In addition, functional analyses provide evidence, that this variant leads to a decreased surface expression and transport activity of SLC1A2.

It was shown that IgG autoantibodies for AQP4 in patients with NMOSD reduce SLC1A2 activity followed by reduced glutamate-reuptake from the synaptic cleft. Thus, our identified variant in SLC1A2 might have a similar effect by causing decreased transport activity. Furthermore, it is known that increased release or decreased reuptake of glutamate leads to an excessive stimulation of glutamate receptors. This results in neurological damage and cell death, a process called excitotoxicity. Hence, there might be a correlation between reduced SLC1A2 activity which results in excessive supply of glutamate in the synaptic cleft and the neurological disorders of the patient described herein.

Our current data are insufficient to assess whether this variant is associated with the symptoms of our patient. Presently his parents are recruited to assess whether this variant occurred de novo. This would support our hypothesis that pathogenic variants in SLC1A2 can be associated with NMOSD.