Localizing MEF more precisely on the basis of homozygosity rates alone would be difficult, for two reasons: First, the high FMF carrier frequency increases the chance that inbred offspring could have the disease without being homozygous by descent at MEF.
Using DNAs from affected Israeli families, we have recently mapped the gene causing FMF (designated MEF) to the short arm of chromosome 16, with two-point lod scores in excess of 20.
Recently, the gene responsible for FMF, denoted pyrin, has been cloned, and three disease mutations have been described (French FMF Consortium, 1997; International FMF Consortium, 1997).
Although we hope the discovery of the FMF gene will allow the diagnosis of FMF to become genetically accurate, the reality is that both clinical and genetic tools must still be used together unless mutations are identified on both of a patient's chromosomes.
The demonstration of both the diagnostic and prognostic value of MEFV analysis and particular modes of inheritance should lead to new ways for management of FMF-including genetic counseling and therapeutic decisions in affected families.
Familial Mediterranean fever (MIM 249100) is an autosomal recessive disorder affecting mostly populations from the Mediterranean basin and is caused by mutations in the gene MEFV (refs 5,6).
A Turkish patient with episodic fever and thoracic pain is described in whom a homozygous M694V mutation of the MEFV gene confirmed the clinical diagnosis of familial Mediterranean fever.
Studies of two further unrelated British patients with FMF associated with simple heterozygosity for pyrinDeltaM694 were also consistent with autosomal dominant inheritance.
Overall, these data, which provide new insights into the pathophysiology of FMF, demonstrate that susceptibility to renal amyloidosis in this Mendelian disorder is influenced by at least two MEFV-independent factors of genetic origin-SAA1 and sex-that act independently of each other.
Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus.