Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay.
Mutations in the SLC13A5 gene that codes for the Na(+)/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In the present study we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and treatment strategies. There are currently no effective treatments, but some anti-epileptic drugs targeting the GABA system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical anti-seizure medication decreases seizures in 4 patients. In contrast to previous reports, the ketogenic diet and fasting produce worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improve transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, our study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na(+)/citrate transporters.
Department of Neurology, Stanford University School of Medicine, Palo Alto, CA 94305.
Jenna
J
Klotz
Department of Neurology, Stanford University School of Medicine, Palo Alto, CA 94305.
Brenda E
BE
Porter
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Claire
C
Colas
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Avner
A
Schlessinger
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego, La Jolla, CA 92130-0718.
Ana M
AM
Pajor
D000293:Adolescent; D000818:Animals; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011485:Protein Binding; D021381:Protein Transport; D027981:Symporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
C470492:SLC13A5 protein, human; D027981:Symporters
citrate; epilepsy; sodium; tooth hypoplasia; transporter