Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures

PLoS One. 2015 Mar 20;10(3):e0118946. doi: 10.1371/journal.pone.0118946. eCollection 2015.

Abstract

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Chloride Channels / chemistry
  • Chloride Channels / genetics*
  • DNA Mutational Analysis
  • Epilepsy, Benign Neonatal / complications*
  • Epilepsy, Benign Neonatal / genetics*
  • Exons / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Mutagenesis
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Seizures, Febrile / complications*
  • Seizures, Febrile / genetics*

Substances

  • CLCN6 protein, human
  • Chloride Channels
  • RNA, Messenger

Grants and funding

This study was partially supported by a Grant-in-Aid for Scientific Research on Innovated Areas "Foundation of Synapse and Neurocircuit Pathology" (23110534); a Grant-in-Aid for scientific research and a Grant-in-Aid of Health Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare, Japan; a Grant from the Mother and Child Health Foundation in Japan; and a Grant from Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics (T.Y.). This study was partially supported by a Grant-in-Aid for Young Scientists (B) (24791090), Japan Society for the Promotion of Science (JSPS), a Grant from the Japan Epilepsy Research Foundation (JERF), and a Grant from Kanae Foundation for the promotion of Medical Science in Japan (K.S.). The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.