Journal Article

Altered Spacing of Promoter Elements Due to the Dodecamer Repeat Expansion Contributes to Reduced Expression of the Cystatin B Gene in EPM1

Maria D. Lalioti, Hamish S. Scott and Stylianos E. Antonarakis

in Human Molecular Genetics

Volume 8, issue 9, pages 1791-1798
Published in print September 1999 | ISSN: 0964-6906
Published online September 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.9.1791
Altered Spacing of Promoter Elements Due to the Dodecamer Repeat Expansion Contributes to Reduced Expression of the Cystatin B Gene in EPM1

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Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder characterized by seizures, myoclonus and progression to cerebellar ataxia. EPM1 arises due to mutations in the cystatin B (CSTB) gene which encodes a cysteine proteinase inhibitor. Only a minority of EPM1 alleles carry point mutations, while the majority contain large expansions of the dodecamer CCCCGCCCCGCG repeat which is present at two to three copies in normal individuals. The dodecamer repeat is located in the 5′ flanking region of the CSTB gene, presumably in its promoter. The pathological repeat expansion results in a reduction in CSTB mRNA, which may be cell specific. To elucidate the mechanism of this reduction of gene expression, we have studied theputativeCSTBpromoter in vitro. A 3.8 kb fragment, containing the putative promoter with a 600 bp repeat expansion, showed a 2-to 4-fold reduction in luciferase activity compared with an identical fragment with a normal repeat; this reduction was observed only in certain cell types. Introduction of heterologous DNA fragments of 730 and 1000 bp into the normal promoter, instead of the repeat expansion, showed similarly reduced activity. Terminal deletions of the promoter implicateaputativeAP-1bindingsite,upstreamofthe repeat, in CSTB transcription activation. We propose that a novel mechanism of pathogenesis, the altering of the spacing of transcription factor binding sites from each other and/or the transcription initiation site due to repeat expansion, is among the causes of reduction in CSTB expression and thus EPM1.

Journal Article.  5685 words.  Illustrated.

Subjects: Genetics and Genomics

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