Characterization of new mutations in the 5′-flanking region of the familial Mediterranean fever gene

• Published in: Genes and immunity Vol. 10; no. 3; pp. 273 - 279
• Main Authors: Notarnicola, C, Boizet-Bonhoure, B, de Santa Barbara, P, Osta, M A, Cattan, D, Touitou, I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2009; Nature Publishing Group; Nature Publishing Group: Open Access Hybrid Model Option B
• Subjects: 5' Untranslated Regions - genetics; Apoptosis; Asymptomatic; Base Sequence; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line; Cell Line, Tumor; Cytokines; Cytoskeletal Proteins - genetics; Deoxyribonucleic acid; Diagnosis; DNA; DNA Mutational Analysis; Exons; Familial Mediterranean fever; Familial Mediterranean Fever - genetics; Female; Fever; Gel electrophoresis; Gene Expression; Gene mapping; Gene mutations; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic screening; Genetics; Health aspects; Human Genetics; Humans; Identification and classification; Immunology; Inflammatory diseases; Investigations; Life Sciences; Male; Molecular Sequence Data; Mutation; Nucleotides; original-article; Pathophysiology; Patients; Population genetics; Promoter Regions, Genetic; Proteins; Pyrin; Pyrin protein; Risk factors; Transcription factors; France; Lebanon; Beirut Lebanon; promoter; FMF; mutations
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2009.8

Familial Mediterranean fever (FMF) is a recessive autoinflammatory disease commonly found in the Mediterranean populations. Genetic diagnosis has developed since the discovery of the causative gene
MEFV
in 1997. As many patients could not be confirmed genetically by routine exon screening, we searched for mutations in the 5′-flanking region of this gene. Using denaturing gradient gel electrophoresis, we screened DNA from 108 patients with clinical FMF and 91 asymptomatic individuals. We found six novel sequence variants in a region extending −825 bp upstream of the first translated codon. To investigate the potential role of these variants in altering
MEFV
gene expression, we first characterized the
MEFV
promoter. Promoter mapping assays revealed that the region located between nucleotides −949 and −152 of the initiation codon was important for regulating expression of the gene. We identified a putative enhancer element between −571 and −414. Investigation of the sequence variants found in two patients demonstrated that c.−614C>G resulted in a 70% decrease in promoter activity, whereas c.−382C>T induced a 100% increase in activity, when compared to the wild type. We observed specific DNA-protein binding to both wild-type sites, suggesting that transcription factors may bind to these sequences to modulate
MEFV
expression.