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Article
Nature Genetics  34, 157 - 165 (2003)
Published online: 5 May 2003; | doi:10.1038/ng1157

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

Cristina Tufarelli, Jackie A Sloane Stanley, David Garrick, Jackie A Sharpe, Helena Ayyub, William G Wood & Douglas R Higgs

MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.

Correspondence should be addressed to Douglas R Higgs drhiggs@molbiol.ox.ac.uk
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.

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REFERENCE
Southern Blotting for the Analysis of Human Disease
Nature Encyclopaedia of Life Sciences

REVIEWS
CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future
Oncogene Reviews (12 Aug 2002)
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NEWS AND VIEWS
Turned off by RNA
Nature Genetics News and Views (01 Jun 2003)

RESEARCH
Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells
Oncogene Original Article (19 Jun 2003)
Expression of alpha- and beta-globin genes occurs within different nuclear domains in haemopoietic cells
Nature Cell Biology Brief Communication (01 Jun 2001)
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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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