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The E148Q mutation in the MEFV gene: is it a disease-causing mutation or a sequence variant?
E Ben-Chetrit1, I Lerer, E Malamud
1Department of Medicine A, Hadassah Hebrew University, Jerusalem, Israel. Eldad@hadassah.org.il
Abstract:
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of serositis. To date more then 18 mutations responsible for the disease were identified in the MEFV gene, one such a mutation is E148Q in exon 2 of the gene. While screening FMF patients for mutations in the MEFV gene, we have identified 2 individuals parents of 2 unrelated FMF patients, who were homozygous for E148Q mutation. Upon clinical examination they were absolutely disease free and therefore raised the possibility that this mutation is a benign polymorphism rather than a mutation causing disease. To further investigate the role of the E148Q in FMF we analyzed 25 parents of FMF patients and a control group of 70 individuals, Jews of Moroccan extraction to match for ethnicity of the patients. The rate of E148Q in the control group was 6.4%, being 7.8% among the patient group. Among the parents group (obligatory carriers), in addition to the 2 parents that were homozygous E148Q, in 2 families one of the parents was heterozygote for E148Q but transmitted the other allele (apparently with unknown FMF mutation) to the affected child. Two healthy sibs of one of the E148Q homozygous were also homozygous E148Q. These observations are not in accordance to the notion that E148Q is a mutation causing disease.
Insights
The E148Q variant in the MEFV gene is frequently found in healthy individuals, suggesting it is a benign polymorphism, not a disease-causing mutation for Familial Mediterranean Fever (FMF). Further research is needed to confirm its role.
Area of Science:
- Genetics
- Molecular Biology
- Immunology
Background:
- Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disorder characterized by recurrent serositis.
- Over 18 MEFV gene mutations are linked to FMF, with E148Q in exon 2 being one identified variant.
Purpose of the Study:
- To investigate the clinical significance of the E148Q variant in the MEFV gene concerning FMF.
- To determine if E148Q represents a disease-causing mutation or a benign polymorphism.
Main Methods:
- Screening FMF patients and their parents for MEFV gene mutations.
- Clinical examination of individuals found to be homozygous for the E148Q variant.
- Analyzing the frequency of the E148Q variant in FMF patients, their parents, and a matched control group (Jews of Moroccan extraction).
Main Results:
- Two parents of unrelated FMF patients were homozygous for E148Q but remained clinically disease-free.
- The E148Q variant was found in 6.4% of the control group and 7.8% of the patient group.
- Homozygous E148Q individuals and their healthy siblings did not exhibit FMF symptoms, challenging its role as a pathogenic mutation.
Conclusions:
- The E148Q variant in the MEFV gene appears to be a benign polymorphism rather than a mutation causing Familial Mediterranean Fever.
- These findings necessitate a re-evaluation of the pathogenicity of the E148Q variant in FMF diagnostics and research.