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

Journal article

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.

Authors: Tufarelli, C; Stanley, J; Garrick, D; Sharpe, J; Ayyub, H

• Publication status: Published
• Journal: Nature genetics
• Volume: 34
• Issue: 2
• Pages: 157-165
• Publication date: 2003-06-01
• DOI: 10.1038/ng1157
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Globins; DNA; Animals; Chromosomes, Human, Pair 16; Mice; Models, Genetic; Cell Line; DNA Methylation; Transcription, Genetic; CpG Islands; Humans; Gene Silencing; alpha-Thalassemia; RNA, Antisense; Mice, Transgenic; Promoter Regions, Genetic; Base Sequence