Myotonic dystrophy: will the real gene please step forward!

Hum Mol Genet. 1996:5 Spec No:1417-23. doi: 10.1093/hmg/5.supplement_1.1417.

Abstract

The mutation underlying myotonic dystrophy (DM) was identified at the end of 1991 amidst great rejoicing from the patients supporting the research and, not least, from those who spent so long searching for it. Subsequently, the molecular genetic phenomena associated with DM have been clearly explained by the transmission behaviour of the expanding repeat, which remains the only mutation that has been described in patients. We understand the molecular basis of anticipation, why the severe congenital form is almost exclusively transmitted by affected mothers and we have widely accepted models of the population genetics of DM. Yet, despite all these clearly explained molecular events, we appear to be hardly any closer to understanding the molecular pathology of DM than when the mutation was first identified. To understand the reason for this, we have to look in detail at the mutation itself, and in particular at the locus and its complex nuances. In doing so, we begin to realise that DM is unique amongst the Mendelianly inherited disorders, in that the mutation, because of its location in a very gene-rich region of the genome, probably simultaneously renders several genes dysfunctional. The somatic heterogeneity of the repeat, coupled with the involvement of several genes, accounts for the pleiotropy observed in the phenotype. Added to this complexity is the uncertainty of the level at which gene dysfunction or gain of function is occurring. It is possibly at the level of DNA/chromatin structure and/or RNA regulation/processing, and all of these pathways may, in different tissues, contribute to the final phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • DNA
  • Disease Models, Animal
  • Genes, Tumor Suppressor
  • Genetics, Population
  • Humans
  • Multigene Family
  • Mutagenesis
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / metabolism
  • Protein Kinases / genetics
  • RNA
  • Repetitive Sequences, Nucleic Acid

Substances

  • RNA
  • DNA
  • Protein Kinases