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

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

I. Aksentijevich et al., 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 HU GEN, 64(4), 1999, pp. 949-962

30

INGLESE

Article

Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics

AMERICAN JOURNAL OF HUMAN GENETICS

0002-9297 → ACNP

64

4

1999

949 - 962

ISI

0002-9297(199904)64:4<949:MAHSOF>2.0.ZU;2-C

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was clo ned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not origina lly found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) i s located in exon 3. Consistent with another recent report, the E148Q mutat ion was observed in patients of several ethnicities and on multiple microsa tellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among similar to 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mut ation. Several lines of evidence indicate reduced penetrance among Ashkenaz i Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps a ccount for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF The presence of three frequ ent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region.