| Structural highlights
Disease
MEFV_HUMAN Defects in MEFV are the cause of familial Mediterranean fever autosomal recessive (ARFMF) [MIM:249100. ARFMF is an inherited disorder characterized by recurrent episodic fever, serosal inflammation and pain in the abdomen, chest or joints. ARFMF is frequently complicated by amyloidosis, which leads to renal failure and can be prophylactically treated with colchicine. ARFMF primarily affects ancestral ethnic groups living around the Mediterranean basin: North African Jews, Armenians, Arabs and Turks. The disease is also distributed in other populations including Greeks, Cypriots, Italians and Spanish, although at a lower prevalence.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Defects in MEFV are the cause of familial Mediterranean fever autosomal dominant (ADFMF) [MIM:134610. ADFMF is characterized by periodic fever, serosal inflammation and pain in the abdomen, chest or joints as seen also in the autosomal recessive form of the disease. It is associated with renal amyloidosis and characterized by colchicine unresponsiveness.
Function
MEFV_HUMAN Probably controls the inflammatory response in myelomonocytic cells at the level of the cytoskeleton organization.[16] [17]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The inherited autoinflammatory syndrome familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, which are independent of any bacterial or viral infections. This disease is associated with point mutations in the mefv gene product pyrin. Although the precise molecular functions of pyrin are unknown, it seems to be involved in the maturation and secretion of interleukin-1beta. Approximately two thirds of all FMF-associated mutations cluster in the C-terminal B30.2 domain of pyrin. To investigate the molecular consequences of FMF-associated mutations, we determined the crystal structure of the pyrin B30.2 domain at 1.35-A resolution. The comparison with other B30.2/ligand complex structures revealed a shallow cavity, which seems to be involved in binding the pyrin ligand. The bottom of this cavity is covered mainly with hydrophobic amino acids, suggesting that pyrin recognizes its ligand by hydrophobic contacts and surface complementarities. FMF-associated mutations cluster around two sites on the B30.2 surface. Approximately two thirds, including those mutations with the most severe disease outcomes, are observed in the vicinity of the predicted peptide binding site, suggesting that they will have a direct impact on ligand binding. A second mutational hot spot was observed on the opposite side of the B30.2 domain in the neighbourhood of its artificial N-terminus. Although most FMF-associated mutations are solvent exposed, several will modify the main-chain conformation of loops. The experimental crystal structure of the pyrin B30.2 domain serves as a basis for an accurate modelling of these mutations.
The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever.,Weinert C, Grutter C, Roschitzki-Voser H, Mittl PR, Grutter MG J Mol Biol. 2009 Nov 27;394(2):226-36. Epub 2009 Aug 31. PMID:19729025[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ . Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell. 1997 Aug 22;90(4):797-807. PMID:9288758
- ↑ . A candidate gene for familial Mediterranean fever. Nat Genet. 1997 Sep;17(1):25-31. PMID:9288094 doi:10.1038/ng0997-25
- ↑ Timmann C, Muntau B, Kuhne K, Gelhaus A, Horstmann RD. Two novel mutations R653H and E230K in the Mediterranean fever gene associated with disease. Mutat Res. 2001 Aug 8;479(1-2):235-9. PMID:11470495
- ↑ Notarnicola C, Didelot MN, Kone-Paut I, Seguret F, Demaille J, Touitou I. Reduced MEFV messenger RNA expression in patients with familial Mediterranean fever. Arthritis Rheum. 2002 Oct;46(10):2785-93. PMID:12384939 doi:10.1002/art.10575
- ↑ Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet V, Ahmed-Arab M, Dross C, Dupont M, Cattan D, Smaoui N, Dode C, Pecheux C, Nedelec B, Medaxian J, Rozenbaum M, Rosner I, Delpech M, Grateau G, Demaille J, Weissenbach J, Touitou I. Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998 Aug;7(8):1317-25. PMID:9668175
- ↑ Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN. Pyrin/marenostrin mutations in familial Mediterranean fever. QJM. 1998 Sep;91(9):603-6. PMID:10024914
- ↑ Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet. 1999 Apr;64(4):949-62. PMID:10090880
- ↑ Cazeneuve C, Sarkisian T, Pecheux C, Dervichian M, Nedelec B, Reinert P, Ayvazyan A, Kouyoumdjian JC, Ajrapetyan H, Delpech M, Goossens M, Dode C, Grateau G, Amselem S. MEFV-Gene analysis in armenian patients with Familial Mediterranean fever: diagnostic value and unfavorable renal prognosis of the M694V homozygous genotype-genetic and therapeutic implications. Am J Hum Genet. 1999 Jul;65(1):88-97. PMID:10364520 doi:S0002-9297(07)63731-8
- ↑ Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A, Schlezinger M, Halpern GJ, Schwabe A, Kastner D, Rotter JI, Fischel-Ghodsian N. Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet. 1999 Apr;7(3):287-92. PMID:10234504 doi:10.1038/sj.ejhg.5200303
- ↑ Akar N, Misiroglu M, Yalcinkaya F, Akar E, Cakar N, Tumer N, Akcakus M, Tastan H, Matzner Y. MEFV mutations in Turkish patients suffering from Familial Mediterranean Fever. Hum Mutat. 2000 Jan;15(1):118-9. PMID:10612841 doi:<118::AID-HUMU29>3.0.CO;2-5 10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU29>3.0.CO;2-5
- ↑ Domingo C, Touitou I, Bayou A, Ozen S, Notarnicola C, Dewalle M, Demaille J, Buades R, Sayadat C, Levy M, Ben-Chetrit E. Familial Mediterranean fever in the 'Chuetas' of Mallorca: a question of Jewish origin or genetic heterogeneity. Eur J Hum Genet. 2000 Apr;8(4):242-6. PMID:10854105 doi:10.1038/sj.ejhg.5200462
- ↑ Dode C, Pecheux C, Cazeneuve C, Cattan D, Dervichian M, Goossens M, Delpech M, Amselem S, Grateau G. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet. 2000 Jun 5;92(4):241-6. PMID:10842288
- ↑ Aldea A, Calafell F, Arostegui JI, Lao O, Rius J, Plaza S, Maso M, Vives J, Buades J, Yague J. The west side story: MEFV haplotype in Spanish FMF patients and controls, and evidence of high LD and a recombination "hot-spot" at the MEFV locus. Hum Mutat. 2004 Apr;23(4):399. PMID:15024744 doi:10.1002/humu.9229
- ↑ Medlej-Hashim M, Serre JL, Corbani S, Saab O, Jalkh N, Delague V, Chouery E, Salem N, Loiselet J, Lefranc G, Megarbane A. Familial Mediterranean fever (FMF) in Lebanon and Jordan: a population genetics study and report of three novel mutations. Eur J Med Genet. 2005 Oct-Dec;48(4):412-20. Epub 2005 Jun 20. PMID:16378925 doi:S1769-7212(05)00104-7
- ↑ Goulielmos GN, Fragouli E, Aksentijevich I, Sidiropoulos P, Boumpas DT, Eliopoulos E. Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF). Biochem Biophys Res Commun. 2006 Jul 14;345(4):1326-32. Epub 2006 May 15. PMID:16730661 doi:S0006-291X(06)01029-1
- ↑ Centola M, Wood G, Frucht DM, Galon J, Aringer M, Farrell C, Kingma DW, Horwitz ME, Mansfield E, Holland SM, O'Shea JJ, Rosenberg HF, Malech HL, Kastner DL. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood. 2000 May 15;95(10):3223-31. PMID:10807793
- ↑ Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM, Aksentijevich I, Kastner DL. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood. 2001 Aug 1;98(3):851-9. PMID:11468188
- ↑ Weinert C, Grutter C, Roschitzki-Voser H, Mittl PR, Grutter MG. The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever. J Mol Biol. 2009 Nov 27;394(2):226-36. Epub 2009 Aug 31. PMID:19729025 doi:10.1016/j.jmb.2009.08.059
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