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Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels – Source: PLoS ONE, Dec 30, 2009

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By Jinong Feng, R Paul St Amand, et al. • • January 8, 2010

[Note: A missense is a mutation in a gene’s coding sequence where one amino acid is substituted for another. To read the full text of this article free, click here.]

Background: Fibromyalgia syndrome (FMS), a common, chronic, widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, has both genetic and environmental contributions.

Patients and their parents have high plasma levels of the chemokines MCP-1 and eotaxin, providing evidence for both a genetic and an immunological / inflammatory origin for the syndrome (Zhang et al., 2008, Exp. Biol. Med. 233: 1171-1180).

Methods and Findings: In a search for a candidate gene affecting inflammatory pathways, among five screened in our patient samples (100 probands [subjects] with FMS and their parents), we found 10 rare and one common alleles for MEFV, a gene in which various compound heterozygous mutations lead to Familial Mediterranean Fever (FMF). [Note: Alleles are different possible sequences of DNA at a specific position on a specific chromosome. Heterozygous means the two inherited alleles for a genetic trait are different, whereas homozygous means both are the same. Mediterranean Fever is an inherited inflammatory disorder prominently found in Mediterranean area peoples.]

A total of 2.63 megabases of genomic sequence of the MEFV gene were scanned by direct sequencing. The collection of rare missense mutations (all heterozygotes and tested in the aggregate) had a significant elevated frequency of transmission to affecteds (p = 0.0085, one-sided, exact binomial test).

Our data provide evidence that:

• Rare missense variants of the MEFV gene are, collectively, associated with risk of FMS

• And are present in a subset of 15% of FMS patients.

This subset had, on average, high levels of plasma IL-1beta (p = 0.019) compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype.

IL-1beta is:

• A cytokine [signaling molecule secreted by the immune system] associated with the function of the MEFV gene,

• And thought to be responsible for its symptoms of fever and muscle aches.

Conclusions: Since misregulation of IL-1beta expression has been predicted for patients with mutations in the MEFV gene, we conclude that patients heterozygous for rare missense variants of this gene may be predisposed to FMS, possibly triggered by environmental factors.

Source: PLoS ONE, Dec 30,2009;4(12) e8480. PMID: 20041150, by Feng J, Zhang Z, Li W, Shen X, Song W, Yang C, Chang F, Longmate J, Marek C, St Amand RP, Krontiris TG, Shively JE, Sommer SS. Division of Molecular Genetics, Beckman Research Institute, City of Hope, Duarte, California, USA. [E-mail: John Shively,]

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