SCREENING AND BIOCHEMICAL-CHARACTERIZATION OF TRANSTHYRETIN VARIANTS IN THE PORTUGUESE POPULATION

The study of pathogenic and nonpathogenic transthyretin (TTR) variants is very important for the understanding of such TTR related diseases as hereditary amyloidosis and also to establish a relationship between the structure and function of the molecule. Variants with clinical ma nifestations can be easily detected, but clinically silent variants ca n be detected only by population screening programs using specialized techniques. Hybrid isoelectric focusing (HIEF) in extremely flattened immobilized pH gradients (IPG) allows the detection of even neutral am inoacid substitutions and has been used to analyze similar to 5,000 sa mples from the Portuguese population. Comparison with samples from car riers of three known TTR mutations (Met 30 associated with hereditary amyloidosis, Met 119, and Asn 90) was also made. In this study we dete cted: (1) 8 individuals carriers of TTR Met 30, (2) 35 carriers of TTR Met 119, (3) 12 carriers of TTR Asn 90, (4) 1 compound heterozygote f or TTR Met 30/Met 119, and (5) 5 variants that presented a different p attern from the controls used, We also performed DNR sequencing analys es of two of the variants with the different band pattern in HIEF. The individuals were found to be carriers of TTR Ile 122 and TTR Thr 109, respectively. All the mutations detected, except for Asn 90, result f rom substitutions in CpG hot spots and thus can be rather frequent in the populations. Studies on the clinical evolution of the compound het erozygotes and on the physical chemical properties of these hybrid TTR s will help to understand the pathogenicity associated with TTR. (C) 1 997 Wiley-Liss, Inc.