Late-onset episodic ataxia associated with SLC1A3 mutation.
Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.
Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea.
Kwang-Dong
KD
Choi
Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.
Joanna C
JC
Jen
Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea.
Seo Young
SY
Choi
Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.
Jin-Hong
JH
Shin
Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.
Hyang-Sook
HS
Kim
Department of Biomedical Laboratory Science, Kyungdong University, Goseong, Korea.
Hyo-Jung
http://orcid.org/0000-0002-2027-6341
HJ
Kim
Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Korea.
Ji-Soo
JS
Kim
Department of Neurology, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea.
Jae-Hwan
JH
Choi
D000086:Acetazolamide / Q000627:therapeutic use; D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000927:Anticonvulsants / Q000627:therapeutic use; D001483:Base Sequence; D002524:Cerebellar Ataxia / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D027341:Excitatory Amino Acid Transporter 1 / Q000737:chemistry / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D014633:Valine / Q000737:chemistry / Q000378:metabolism*
D000927:Anticonvulsants; D027341:Excitatory Amino Acid Transporter 1; C493394:SLC1A3 protein, human; D007532:Isoleucine; D014633:Valine; D000086:Acetazolamide