Expression of the familial Mediterranean fever gene is regulated by nonsense-mediated decay.

Hum Mol Genet 2009 Dec 15;18(24):4746-55. Epub 2009 Sep 15.

Génétique des Maladies Auto-Inflammatoires, Institut de Génétique Humaine, CNRS-UPR1142, Montpellier, France.

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.

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http://dx.doi.org/10.1093/hmg/ddp437DOI Listing
December 2009
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References

(Supplied by CrossRef)
A candidate gene for familial Mediterranean fever
Consortium et al.
Nat. Genet. 1997
MEFV gene 3′-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever
Ustek et al.
Clin. Exp. Rheumatol. 2008
The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators
Centola et al.
Blood 2000
Hematopoietic-specific expression of MEFV, the gene mutated in familial Mediterranean fever, and subcellular localization of its corresponding protein, pyrin
Tidow et al.
Blood 2000

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