Independent Occurrence of the CHRNA4 Ser248Phe Mutation in a Norwegian Family with Nocturnal Frontal Lobe Epilepsy

Authors

  • Ortrud K. Steinlein,

    Corresponding author
    1. Institute for Human Genetics, Friedrich-Wilhelms-University of Bonn, Bonn, Germany
      Address correspondence and reprint requests to Dr. O. K. Steinlein at Institute for Human Genetics, University of Bonn, Wilhelmstr. 31, D-53111 Bonn, Germany. E-mail: osteinl@mailer.meb.uni-bonn.de
    Search for more papers by this author
  • Jens Stoodt,

    1. Institute for Human Genetics, Friedrich-Wilhelms-University of Bonn, Bonn, Germany
    Search for more papers by this author
  • John Mulley,

    1. Department of Cytogenetics and Molecular Genetics, Women's and Children's Hospital and Department of Genetics, University of Adelaide, Adelaide
    Search for more papers by this author
  • Sam Berkovic,

    1. Department of Neurology, University of Melbourne, Austin and Repatriation Medical Centre, and Royal Children's Hospital, Melbourne, Australia
    Search for more papers by this author
  • Ingrid E. Scheffer,

    1. Department of Neurology, University of Melbourne, Austin and Repatriation Medical Centre, and Royal Children's Hospital, Melbourne, Australia
    Search for more papers by this author
  • Eylert Brodtkorb

    1. Department of Neurology, Trondheim University Hospital, Trondheim, Norway
    Search for more papers by this author

Address correspondence and reprint requests to Dr. O. K. Steinlein at Institute for Human Genetics, University of Bonn, Wilhelmstr. 31, D-53111 Bonn, Germany. E-mail: osteinl@mailer.meb.uni-bonn.de

Abstract

Summary: Purpose: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is associated with a Ser248Phe amino acid exchange in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor α4 subunit (CHRNA4). We also tested for evidence of a de novo mutation or founder effect by comparing haplotypes with the original Australian family where the Ser248Phe mutation was first described.

Methods: Clinical details were obtained from 19 family members. Personal interviews and genetic analysis were carried out in 17. Parts of the coding region of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp594/CfoI) were typed by restriction analysis.

Results: Eleven individuals had ADNFLE. The haplotypes of the mutation-carrying alleles of affected individuals from the Northern Norwegian and the Australian ADNFLE family are different. The phenotypic expressions are remarkably similar.

Conclusions: The Ser248Phe mutation occurred independently in both families. Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid exchange is important for the etiology of ADNFLE. The phenotypic similarity of these two families with different genetic backgrounds suggests that the Ser248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.

Ancillary