Human Molecular Genetics Advance Access published online on January 13, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh053
© 2004 by Oxford University Press
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1 Department of Biological Chemistry, University of California, Davis, School of Medicine, Davis, CA, USA
* To whom correspondence should be addressed. E-mail: pjhagerman{at}ucdavis.edu.
Fragile X syndrome, the most common form of mental impairment, is caused by expansion of a (CGG)n trinucleotide repeat element located in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. Repeat expansion is known to influence both transcription and translation; however, the mechanisms by which the CGG element exerts its effects are not known. In the current work, we have utilized 5'RLM-RACE to examine the influence of CGG repeat number on the utilization of transcription start sites in normal (n < 55) and premutation (54 < n < 200) cell lines of both non-neural (lymphoblastoid) and neural (primary astrocyte) origin. Our results demonstrate that in both neural and non-neural cells, transcription of the FMR1 gene is initiated from several transcription start sites within a
Article
Redistribution of transcription start sites within the FMR1 promoter region with expansion of the downstream CGG-repeat element
2 Children's Hospital of Orange County Research Institute, Orange, CA, USA
3 Department of Biological Chemistry, University of California, Davis, School of Medicine, One Shields Avenue, Davis, CA 95616, USA
Abstract 
50 nucleotide (nt) region that lies 130 nt upstream of the CGG repeat element. For normal alleles, most transcripts initiate from the downstream-most start site, close to the single position identified previously. Surprisingly, as the size of the CGG repeat expands into the premutation range, initiation shifts to the upstream sites, suggesting that the CGG element may act as a downstream enhancer/modulator of transcription. The shift in start site selection for both neural and non-neural cells indicates that the effect is general. Furthermore, the correspondence between start site utilization and the degree of elevation of FMR1 mRNA suggests that a substantial fraction of the increased message in the premutation range may derive from the upstream start sites.
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