Role of E148Q in familial Mediterranean fever with an exon 10 mutation in MEFV

Abstract

Background Familial Mediterranean fever (FMF) is an autosomal recessive disease caused by mutations in the MEFV gene. Mutations in exon 10 are associated with typical FMF. Most Japanese patients with typical FMF are compound heterozygotes of M694I in exon 10 and E148Q in exon 2. However, the pathogenic role of E148Q remains controversial. Methods We assessed symptoms and serum cytokines among patients with FMF and their family members. They were divided into three subgroups, based on MEFV mutations: individuals carrying M694I and E148Q (group A, n = 14), individuals carrying M694I, but not E148Q (group B, n = 10), and individuals carrying E148Q, but not M694I (group C, n = 11). Results All but one individual in group A had typical FMF phenotypes, whereas no individual in groups B and C exhibited any episodes of fever or serositis. The serum levels of interleukin‐18 during the afebrile phase were significantly elevated in group A (2,806 ± 2,107 pg/mL), compared to those in groups B (499 ± 369 pg/mL) and C (427 ± 410 pg/mL). No difference in interleukin‐6 levels was observed among the three groups. Conclusions These findings indicated that E148Q may contribute to disease development of FMF in Japanese patients carrying the heterozygous M694I mutation in MEFV and that genetic testing of both parents would lead to better counseling for their children.

IgA Vasculitis in Japanese Patients Harboring MEFV Mutations: A Case Report and Review of the Literature

“…Familial Mediterranean fever is a genetic abnormality associated with inflammasome, and patients with this condition present with high serum IL-1β and IL-18 levels [11,14,20]. In particular, FMF with M694I mutation is associated with high IL-18 levels even in the intermittent afebrile phase [11,20]. In the current case, the serum IL-18 levels of our patient were higher than those of other patients with IgAV, and they decreased with the administration of colchicine.…”

“…This is because she did not have recurrent febrile episodes. FMF may develop in adulthood, and the IL-18 concentration in this patient is still high even though asymptomatic [11,20]. Therefore, she should be monitored for periodic febrile episodes in the future.…”

“…Familial Mediterranean fever is a genetic abnormality associated with inflammasome, and patients with this condition present with high serum IL-1β and IL-18 levels [11,14,20]. In particular, FMF with M694I mutation is associated with high IL-18 levels even in the intermittent afebrile phase [11,20].…”

Pathogenic roles and diagnostic utility of interleukin-18 in autoinflammatory diseases

“…PSTPIP1 interacts with the actin cytoskeleton by regulating the Wiskott-Aldrich Syndrome protein (119,120) syndrome similar to those in patients with MAS associated with s-JIA and AOSD (36). Serum IL-18 levels were significantly elevated in some patients with familial Mediterranean fever (FMF), although they were not significantly elevated in most patients with FMF (36,121). A recent report revealed FMF patients carrying M694I and E148Q mutations in the MEFV gene had significantly higher levels of serum IL-18 compared with those carrying M694I, but not E148Q, and those carrying E148Q, but not M694I (121).…”

“…Serum IL-18 levels were significantly elevated in some patients with familial Mediterranean fever (FMF), although they were not significantly elevated in most patients with FMF (36,121). A recent report revealed FMF patients carrying M694I and E148Q mutations in the MEFV gene had significantly higher levels of serum IL-18 compared with those carrying M694I, but not E148Q, and those carrying E148Q, but not M694I (121). Although the specific mechanism driving IL-18 through the pyrin inflammasome remains unknown, the dysregulation of interactions between pyrin and PSTPIP1 caused by MEFV and pstpip1 gene mutations might induce the overproduction of IL-18.…”