Vol.22 No.1

Original Article

Enhanced exon 2 skipping caused by c.910G>A variant and alternative splicing of MEFV genes in two independent cases of familial Mediterranean fever

Authors

Yumi Tone1 , Tomoko Toma1 , Akiko Toga1 , Yasuhisa Sakakibara1 , Taizo Wada1 , Masahiro Yabe2 , Hiromitu Kusafuka3 , Akihiro Yachie1

  • Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
  • Department of General Internal Medicine, Niigata City General Hospital, Niigata, Japan
  • Department of General Internal Medicine, Nagoya Memorial Hospital, Nagoya, Japan
Received:

4 April 2011

Accepted:

15 April 2011

Published online:

12 May 2011

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Abstract

Most reported cases of familial Mediterranean fever (FMF) involve missense mutations of MEFV concentrated within exon 10. We experienced two independent pedigrees of a unique variant in the MEFV gene that might cause excessive exon 2 skipping due to enhanced alternative splicing. In this study, we tried to elucidate the molecular mechanism of the MEFV variant as a cause of the FMF phenotype. Peripheral blood was obtained from volunteers and two patients with homozygous c.910G>A variant of the MEFV gene. MEFV messenger RNA (mRNA) expression patterns in mononuclear cells and granulocytes were compared using forward and reverse primers from exons 1 and 3, respectively. Expression profiles of pyrin were examined by transfecting wild-type and variant MEFV genes into HEK293T cells. Expression of normal-sized mRNA was extremely reduced in these patients, whereas that of aberrant short mRNA, deleting exon 2 (Δex2), was significantly increased. Immunohistochemical and immunoblotting analyses revealed a truncated immunoreactive pyrin protein in cells transfected with Δex2 cDNA. The MEFV gene c.910G>A variant results in accelerated aberrant splicing with abnormal protein size, presumably leading to anomalous pyrin function. This is the first report to show that an MEFV variant other than missense mutation is responsible for the FMF phenotype.

Key words

Familial Mediterranean fever - MEFV - Splice anomaly - Pyrin