DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy

Neurology. 2014 Jun 10;82(23):2101-6. doi: 10.1212/WNL.0000000000000488. Epub 2014 May 9.

Abstract

Objective: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

Methods: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells.

Results: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant.

Conclusions: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 22 / genetics
  • Drug Resistance / genetics
  • Epilepsy, Frontal Lobe / genetics
  • Europe
  • Exome / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Repressor Proteins / genetics*

Substances

  • DEPDC5 protein, human
  • Repressor Proteins

Supplementary concepts

  • Autosomal Dominant Nocturnal Frontal Lobe Epilepsy