Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M

Recently a new nonpathogenic transthyretin (TTR) variant-TTR R104H (TTR H10 4)-has been described in heterozygotic and compound heterozygotic individua ls from a Japanese family with familial amyloidotic polyneuropathy (FAP). T he compound heterozygotic individual, a carrier of TTR V30M (TTR M30) and T TR R104H (TTR M30/H104) presented a very mild form of FAP with slow progres sion of the disease. TTR and retinol binding protein (RBP) levels were foun d to be increased in serum from TTR H104 carriers. These characteristics ar e very similar to those found in compound heterozygotic carriers of TTR V30 M-T119M (TTR M30/M119). To structurally compare these variants, we performe d stability and thyroxine (T-4) binding studies. TTR M30/H104 showed an inc reased resistance to dissociation into monomers similar to TTR M30/M119. Th is suggests that the His104 substitution has the same stabilizing effect on tetrameric TTR as the Met119 substitution. Concerning T-4 binding, TTR H10 4 presents a T-4 binding affinity lower than that of TTR M119, but still hi gher than normal TTR, However, TTR from the compound heterozygotic carrier of TTR M30/H104 presented a T-4 binding affinity lower than normal. The res ults indicate that the His 104 substitution induces structural alterations that increase the stability of the tetramer in compound heterozygotes for T TR M30 despite a lower affinity for T-4 binding. Thus, stability of TTR and binding affinity for T-4 may not be related. More detailed characterizatio n of these variants is needed to clarify the structural alterations respons ible for their increased stability. (C) 2000 Academic Press.