Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF)

Abstract

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurring attacks of fever and serositis. It affects primarily North African Jews, Armenians, Turks and Arabs, in which a founder effect has been demonstrated. The marenostrin-pyrin-encoding gene has been proposed as a candidate gene for the disease ( MEFV ), on the basis of the identification of putative mutations clustered in exon 10 (M680V, M694I, M694V and V726A), each segregating with one ancestral haplotype. In a search for additional MEFV mutations in 120 apparently non-founder FMF chromosomes, we observed eight novel mutations in exon 2 (E148Q, E167D and T267I), exon 5 (F479L) and exon 10 (I692del K695R, A744S and R761H). Except for E148Q and K695R, all mutations were found in a single chromosome. Mutation E148Q was found in all ethnic groups studied and in association with a novel ancestral haplotype in non-Ashkenazi Jews (S2). Altogether, these new findings definitively establish the marenostrin/pyrin-encoding gene as the MEFV locus.

Genotype–phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations

“…11 Patient samples were then tested for the 12 most common mutations within the Armenian population. The FMF StripAssay, 12,13 which is based on the reversehybridization principle, was used to identify the following 12 MEFV mutations: E148Q, P369S, F479L, M680I (G/C), M680I (G/A), I692del, M694V, M694I, K695R, V726A, A744S and R761H. A total of 63 samples, 20 homozygous or compound heterozygous, 23 heterozygous and 20 asymptomatic wild-type controls, were selected and their MEFV gene was completely sequenced independently in the United States using dideoxy termination methodology on an ABI 3100 capillary electrophoresis instrument (Appliedbiosystems Inc., Carlsbad, CA, USA).…”

De novo assembly and phasing of a Korean human genome

“…For example, we were able to phase two genes that contained more than two nonsynonymous, heterozygous alleles known to be associated with recessive diseases (Supplementary Table 21). Variants in MEFV 18 and ADAMTS13 (ref. 19), which are predicted to cause familial Mediterranean fever and Upshaw-Shalman syndrome under the autosomal recessive inheritance pattern, respectively, were found in cis configuration, with the partner haplotype left intact.…”

Familial Mediterranean Fever in the World

“…Subsequently, the p.E148Q sequence alteration was identified on exon 2 (19). These were found to be the most common mutations among the populations of the countries where FMF is prevalent.…”