Human Molecular Genetics Advance Access originally published online on September 15, 2009
Human Molecular Genetics 2009 18(24):4746-4755; doi:10.1093/hmg/ddp437
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Expression of the familial Mediterranean fever gene is regulated by nonsense-mediated decay
1 Génétique des maladies Auto-inflammatoires, Institut de Génétique Humaine, CNRS-UPR1142, Montpellier 34296, France, 2 Unité médicale des maladies Auto-inflammatoires, CHRU Montpellier 34295, France and 3 Université Montpellier 1, Montpellier 34967, France
* To whom correspondence should be addressed at: Unité médicale des maladies Auto-inflammatoires, Hôpital A. de Villeneuve, 371, avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France. Tel: +33 467335857; Fax: +33 467335867; Email: isabelle.touitou{at}igh.cnrs.fr
Received April 29, 2009; Accepted September 13, 2009
Mutations in the MEditerranean FeVer (MEFV) gene are responsible for familial Mediterranean fever (FMF), a recessively inherited auto-inflammatory disease. Cases of dominant inheritance and phenotype–genotype heterogeneity have been reported; however, the underlying molecular mechanism is not currently understood. The FMF protein named pyrin or marenostrin (P/M) is thought to be involved in regulating innate immunity but its function remains subject to controversy. Recent studies postulate that a defect in MEFV expression regulation may play a role in FMF physiopathology. Our group, along with others, has identified several alternatively spliced MEFV transcripts in leukocytes. Since alternative splicing and nonsense-mediated decay (NMD) pathways are usually coupled in the post-transcriptional regulation of gene expression, we hypothesized that NMD could contribute to the regulation of the MEFV gene. To address this issue, we examined the effect of indirect and direct inhibition of NMD on expression of the MEFV transcripts in THP1, monocyte and neutrophil cells. We showed that MEFV is the first auto-inflammatory gene regulated by NMD in both a cell- and transcript-specific manner. These results and preliminary western-blot analyses suggest the possible translation of alternatively spliced MEFV transcripts into several P/M variants according to cell type and inflammatory state. Our results introduce the novel hypothesis that variation of NMD efficiency could play an important role in FMF physiopathology as a potent phenotypic modifier.
The nucleotide sequence data reported in this article have been submitted to GenBank and assigned the accession numbers: FJ785717
[GenBank]
(transcript del234) and FJ785722
[GenBank]
(transcript 2
/9ext).