EXPRESSION AND SEQUENCE OF THE GENE FOR TISSUE INHIBITOR OF METALLOPROTEINASES IN PATIENTS WITH ABDOMINAL AORTIC-ANEURYSMS

Purpose: The tissue inhibitors of metalloproteinases (TIMPs) are major inhibitors of several enzymes that are destructive to connective tiss ue, and TIMP-1 has been reported to be deficient in the wall of abdomi nal aortic aneurysms. This deficiency could represent failure of expre ssion resulting from either local tissue conditions or mutation in the primary structure of the gene (or one of its regulatory elements). Me thods: Southern blotting techniques were used to examine the possibili ty of global deletions or inserts in the gene (14 patients); Northern blot techniques were performed to examine the expression of the mRNAs in cultured fibroblasts under basal conditions (six patients); and seq uence analysis of the cDNA derived from fibroblast mRNAs was done afte r amplification by polymerase chain reaction (six patients). Results. The Southern blots revealed a normal distribution of the known alleles of the gene without unique restriction-length polymorphisms. Fibrobla st expression of TIMP mRNA was normal under basal conditions. Sequence analysis of the cDNAs revealed an identical-point polymorphism in two of the six patients (a single base pair substitution of C --> T at th e third position in codon 101), but the amino acid was conserved. Conc lusion: The studies reported here do not support the hypothesis that d eficiency of TIMP-I in specimens of aorta of patients with abdominal a ortic aneurysms results from a primary genetic defect.