COMPARATIVE STABILITY AND CLEARANCE OF [MET30]TRANSTHYRETIN AND [MET119]TRANSTHYRETIN

[Met119]Transthyretin has been described as a non-amyloidogenic transt hyretin variant. In Portugal, it has also been found in compound heter ozygotic individual carriers of [Met30]transthyretin, the most prevale nt variant associated with familial amyloidotic polyneuropathy. In the se individuals, the evolution of the disease seems to be more benign t han in typical [Met30]transthyretin carriers, suggesting a protective effect of [Met119]transthyretin on the pathogenic effects of [Met30]tr ansthyretin. To study the mechanisms of this protective effect, we per formed comparative in vivo clearance studies. Heterotetrameric [Met119 ]transthyretin showed a slower clearance, whereas homotetrameric [Met3 0]transthyretin presented a faster clearance. These data correlate wit h the relative TTR levels present in carriers of these mutations. Comp arative analyses of the resistance to dissociation into monomers of se rum transthyretin by 4M urea isoelectric focusing suggested a higher t etrameric stability of transthyretin in [Met119]transthyretin carriers , in contrast to a lower stability in [Met30]transthyretin carriers. T he compound heterozygores presented a pattern similar to the normal in dividuals. Our results suggest that the protective clinical effect of the Met119 mutation possibly involves the stabilisation of the tetrame ric structure of transthyretin. Whether this behaviour correlates with the different metabolism found for the two variants is not known. The approaches reported here open some possibilities for the study and de velopment of future therapeutic agents of familial amyloidotic polyneu ropathy.