Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease

Nat Genet. 2003 Jun;34(2):157-65. doi: 10.1038/ng1157.


Nearly all human genetic disorders result from a limited repertoire of mutations in an associated gene or its regulatory elements. We recently described an individual with an inherited form of anemia (alpha-thalassemia) who has a deletion that results in a truncated, widely expressed gene (LUC7L) becoming juxtaposed to a structurally normal alpha-globin gene (HBA2). Although it retains all of its local and remote cis-regulatory elements, expression of HBA2 is silenced and its CpG island becomes completely methylated early during development. Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island. These findings identify a new mechanism underlying human genetic disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Chromosomes, Human, Pair 16 / genetics
  • CpG Islands
  • DNA / genetics
  • DNA Methylation*
  • Gene Silencing*
  • Globins / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Promoter Regions, Genetic
  • RNA, Antisense / genetics*
  • Transcription, Genetic
  • alpha-Thalassemia / genetics*


  • RNA, Antisense
  • Globins
  • DNA