Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

Nat Genet. 2018 Apr;50(4):581-590. doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.

Abstract

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Autoantigens / genetics
  • Base Sequence
  • DNA Repeat Expansion*
  • Epilepsies, Myoclonic / etiology
  • Epilepsies, Myoclonic / genetics*
  • Epilepsies, Myoclonic / pathology
  • Female
  • Genomic Instability
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Introns
  • Male
  • Microsatellite Repeats*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Purkinje Cells / pathology
  • RNA-Binding Proteins / genetics
  • Sequence Analysis, DNA
  • Sterile Alpha Motif / genetics*

Substances

  • Autoantigens
  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • RAPGEF2 protein, human
  • RNA-Binding Proteins
  • SAMD12 protein, human
  • TNRC6A protein, human